A Comprehensive Review of Alzheimer’s Association with Related Proteins: Pathological Role and Therapeutic Significance

Deepak       Kumar; Aditi       Sharma; Lalit       Sharma
Abstract

Alzheimer’s is an insidious, progressive, chronic neurodegenerative disease which causes the devastation of neurons. Alzheimer's possesses complex pathologies of heterogeneous nature counting proteins as one major factor along with enzymes and mutated genes. Proteins such as amyloid precursor protein (APP), apolipoprotein E (ApoE), presenilin, mortalin, calbindin-D28K, creactive protein, heat shock proteins (HSPs), and prion protein are some of the chief elements in the foremost hypotheses of AD like amyloid-beta (Aβ) cascade hypothesis, tau hypothesis, cholinergic neuron damage, etc. Disturbed expression of these proteins results in synaptic dysfunction, cognitive impairment, memory loss, and neuronal degradation. On the therapeutic ground, attempts of developing anti-amyloid, anti-inflammatory, anti-tau therapies are on peak, having APP and tau as putative targets. Some proteins, e.g., HSPs, which ameliorate oxidative stress, calpains, which help in regulating synaptic plasticity, and calmodulin-like skin protein (CLSP) with its neuroprotective role are few promising future targets for developing anti-AD therapies. On diagnostic grounds of AD C-reactive protein, pentraxins, collapsin response mediator protein-2, and growth-associated protein-43 represent the future of new possible biomarkers for diagnosing AD. The last few decades were concentrated over identifying and studying protein targets of AD. Here, we reviewed the physiological/pathological roles and therapeutic significance of nearly all the proteins associated with AD that addresses putative as well as probable targets for developing effective anti-AD therapies.
Keywords: Alzheimer`s, neurodegeneration, proteins, pathological role, therapeutics.
Graphical Abstract

[1] 
Scheltens, P.; Blennow, K.; Breteler, M.M.; de Strooper, B.; Frisoni, G.B.; Salloway, S.; Van der Flier, W.M. Alzheimer’s disease. Lancet,  2016, 388(10043), 505-517.
[http://dx.doi.org/10.1016/S0140-6736(15)01124-1] [PMID:  26921134] 
[2] 
World Health Organization and Alzheimer’s Disease International. Dementia: a public health priority., 2012.
[3] 
WHO. Dementia Fact sheet., 2017.https://www.who.int/en/news-room/fact-sheets/detail/dementia  (accessed 8 April 2019)
[4] 
Alzheimer’s & Related Disorders Society of India. The Dementia India Report: prevalence, impact, costs and services for Dementia: Executive Summary; ARDSI: New Delhi, 2010. 
[5] 
Alzheimer’s Association. 2018 Alzheimer’s disease Facts and Figures. Alzheimers Dement.,  2018, 14, 367-429.
[http://dx.doi.org/10.1016/j.jalz.2018.02.001] 
[6] 
Prince, M.; Wimo, A.; Guerchet, M.; Ali, G.C.; Wu, Y.T.; Prina, M. World Alzheimer Report 2015; The Global Impact of Dementia:
	An analysis of prevalence, incidence, cost & trends; ; Alzheimer’s
	disease International, London.. , 2015. 
[7] 
Patterson, C. The State of the Art of Dementia Research: new frontiers; Alzheimer’s disease International, London.,. , 2018. 
[8] 
Schultz, S.A.; Gordon, B.A.; Mishra, S.; Su, Y.; Perrin, R.J.; Cairns, N.J.; Morris, J.C.; Ances, B.M.; Benzinger, T.L.S. Widespread distribution of tauopathy in preclinical Alzheimer’s disease. Neurobiol. Aging,  2018, 72, 177-185.
[http://dx.doi.org/10.1016/j.neurobiolaging.2018.08.022] [PMID:  30292840] 
[9] 
Du, X.; Wang, X.; Geng, M. Alzheimer’s disease hypothesis and related therapies. Transl. Neurodegener.,  2018, 7, 2.
[http://dx.doi.org/10.1186/s40035-018-0107-y] [PMID:  29423193] 
[10] 
Cummings, J.; Aisen, P.S.; DuBois, B.; Frölich, L.; Jack, C.R., Jr; Jones, R.W.; Morris, J.C.; Raskin, J.; Dowsett, S.A.; Scheltens, P. Drug development in Alzheimer’s disease: the path to 2025. Alzheimers Res. Ther.,  2016, 8, 39.
[http://dx.doi.org/10.1186/s13195-016-0207-9] [PMID:  27646601] 
[11] 
Maccarrone, M.; Totaro, A.; Leuti, A.; Giacovazzo, G.; Scipioni, L.; Mango, D.; Coccurello, R.; Nisticò, R.; Oddi, S. Early alteration of distribution and activity of hippocampal type-1 cannabinoid receptor in Alzheimer’s disease-like mice overexpressing the human mutant amyloid precursor protein. Pharmacol. Res.,  2018, 130, 366-373.
[http://dx.doi.org/10.1016/j.phrs.2018.02.009] [PMID:  29454025] 
[12] 
Brier, M.R.; Gordon, B.; Friedrichsen, K.; McCarthy, J.; Stern, A.; Christensen, J.; Owen, C.; Aldea, P.; Su, Y.; Hassenstab, J.; Cairns, N.J.; Holtzman, D.M.; Fagan, A.M.; Morris, J.C.; Benzinger, T.L.; Ances, B.M. Tau and Aβ imaging, CSF measures, and cognition in Alzheimer’s disease. Sci. Transl. Med.,  2016, 8(338), 338ra66.
[http://dx.doi.org/10.1126/scitranslmed.aaf2362] [PMID:  27169802] 
[13] 
Ahmadi, S.; Ebralidze, I.; She, Z.; Kraatz, H.B. Electrochemical studies of tau protein-iron interactions − potential implications for Alzheimer’s disease. Electrochim. Acta,  2017, 236, 384-393.
[http://dx.doi.org/10.1016/j.electacta.2017.03.175] 
[14] 
Hashimoto, Y.; Nawa, M.; Kurita, M.; Tokizawa, M.; Iwamatsu, A.; Matsuoka, M. Secreted calmodulin-like skin protein inhibits neuronal death in cell-based Alzheimer’s disease models via the heterotrimeric Humanin receptor. Cell Death Dis.,  2013, 4, e555.
[http://dx.doi.org/10.1038/cddis.2013.80] [PMID:  23519124] 
[15] 
Toda, T.; Noda, Y.; Ito, G.; Maeda, M.; Shimizu, T. Presenilin-2 mutation causes early amyloid accumulation and memory impairment in a transgenic mouse model of Alzheimer’s disease. J. Biomed. Biotechnol.,  2011, 2011, 617974.
[http://dx.doi.org/10.1155/2011/617974] [PMID:  21234330] 
[16] 
Abad, M.A.; Enguita, M.; DeGregorio-Rocasolano, N.; Ferrer, I.; Trullas, R. Neuronal pentraxin 1 contributes to the neuronal damage evoked by amyloid-beta and is overexpressed in dystrophic neurites in Alzheimer’s brain. J. Neurosci.,  2006, 26(49), 12735-12747.
[http://dx.doi.org/10.1523/JNEUROSCI.0575-06.2006] [PMID:  17151277] 
[17] 
Hiltunen, M.; Lu, A.; Thomas, A.V.; Romano, D.M.; Kim, M.; Jones, P.B.; Xie, Z.; Kounnas, M.Z.; Wagner, S.L.; Berezovska, O.; Hyman, B.T.; Tesco, G.; Bertram, L.; Tanzi, R.E. Ubiquilin 1 modulates amyloid precursor protein trafficking and Abeta secretion. J. Biol. Chem.,  2006, 281(43), 32240-32253.
[http://dx.doi.org/10.1074/jbc.M603106200] [PMID:  16945923] 
[18] 
Scarpini, E.; Scheltens, P.; Feldman, H. Treatment of Alzheimer’s disease: current status and new perspectives. Lancet Neurol.,  2003, 2(9), 539-547.
[http://dx.doi.org/10.1016/S1474-4422(03)00502-7] [PMID:  12941576] 
[19] 
Alzheimer’s Association; Medications for Memory., 2018.https://alz.org/alzheimers-dementia/treatments/medications-for-memory(accessed 8 April 2019) . 
[20] 
Cummings, J.; Lee, G.; Ritter, A.; Sabbagh, M.; Zhong, K. Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement. (N. Y.),  2019, 5, 272-293.
[http://dx.doi.org/10.1016/j.trci.2019.05.008] [PMID:  31334330] 
[21] 
Priller, C.; Bauer, T.; Mitteregger, G.; Krebs, B.; Kretzschmar, H.A.; Herms, J. Synapse formation and function is modulated by the amyloid precursor protein. J. Neurosci.,  2006, 26(27), 7212-7221.
[http://dx.doi.org/10.1523/JNEUROSCI.1450-06.2006] [PMID:  16822978] 
[22] 
Tharp, W.G.; Sarkar, I.N. Origins of amyloid-β. BMC Genomics,  2013, 14, 290.
[http://dx.doi.org/10.1186/1471-2164-14-290] [PMID:  23627794] 
[23] 
Vanden Dries, V.; Stygelbout, V.; Pierrot, N.; Yilmaz, Z.; Suain, V.; De Decker, R.; Buée, L.; Octave, J.N.; Brion, J.P.; Leroy, K. Amyloid precursor protein reduction enhances the formation of neurofibrillary tangles in a mutant tau transgenic mouse model. Neurobiol. Aging,  2017, 55, 202-212.
[http://dx.doi.org/10.1016/j.neurobiolaging.2017.03.031] [PMID:  28464981] 
[24] 
Zheng, H.; Koo, E.H. Biology and pathophysiology of the amyloid precursor protein. Mol. Neurodegener.,  2011, 6(1), 27.
[http://dx.doi.org/10.1186/1750-1326-6-27] [PMID:  21527012] 
[25] 
Cho, H.; Lee, H.S.; Choi, J.Y.; Lee, J.H.; Ryu, Y.H.; Lee, M.S.; Lyoo, C.H. Predicted sequence of cortical tau and amyloid-β deposition in Alzheimer disease spectrum. Neurobiol. Aging,  2018, 68, 76-84.
[http://dx.doi.org/10.1016/j.neurobiolaging.2018.04.007] [PMID:  29751288] 
[26] 
Hamley, I.W. The amyloid beta peptide: a chemist’s perspective. Role in Alzheimer’s and fibrillization. Chem. Rev.,  2012, 112(10), 5147-5192.
[http://dx.doi.org/10.1021/cr3000994] [PMID:  22813427] 
[27] 
Entrez Gene: APOE apolipoprotein E [Homo sapiens (human)]. https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=348  (accessed 8 April 2019)
[28] 
Liu, C.C.; Liu, C.C.; Kanekiyo, T.; Xu, H.; Bu, G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat. Rev. Neurol.,  2013, 9(2), 106-118.
[http://dx.doi.org/10.1038/nrneurol.2012.263] [PMID:  23296339] 
[29] 
Huang, Y. Apolipoprotein E and Alzheimer disease. Neurology,  2006, 66(2)(Suppl. 1), S79-S85.
[http://dx.doi.org/10.1212/01.wnl.0000192102.41141.9e] [PMID:  16432152] 
[30] 
Elshourbagy, N.A.; Liao, W.S.; Mahley, R.W.; Taylor, J.M. Apolipoprotein E mRNA is abundant in the brain and adrenals, as well as in the liver, and is present in other peripheral tissues of rats and marmosets. Proc. Natl. Acad. Sci. USA,  1985, 82(1), 203-207.
[http://dx.doi.org/10.1073/pnas.82.1.203] [PMID:  3918303] 
[31] 
Beffert, U.; Poirier, J. Apolipoprotein E, plaques, tangles and cholinergic dysfunction in Alzheimer’s disease. Ann. N. Y. Acad. Sci.,  1996, 777, 166-174.
[http://dx.doi.org/10.1111/j.1749-6632.1996.tb34415.x] [PMID:  8624080] 
[32] 
Han, S.H.; Einstein, G.; Weisgraber, K.H.; Strittmatter, W.J.; Saunders, A.M.; Pericak-Vance, M.; Roses, A.D.; Schmechel, D.E. Apolipoprotein E is localized to the cytoplasm of human cortical neurons: a light and electron microscopic study. J. Neuropathol. Exp. Neurol.,  1994, 53(5), 535-544.
[http://dx.doi.org/10.1097/00005072-199409000-00013] [PMID:  8083695] 
[33] 
Wang, S.; Zhang, J.; Pan, T. for Alzheimer’s Disease Neuroimaging Initiative. APOE ε4 is associated with higher levels of CSF SNAP-25 in prodromal Alzheimer’s disease. Neurosci. Lett.,  2018, 685, 109-113.
[http://dx.doi.org/10.1016/j.neulet.2018.08.029] [PMID:  30144541] 
[34] 
Nyarko, J.N.K.; Quartey, M.O.; Pennington, P.R.; Heistad, R.M.; Dea, D.; Poirier, J.; Baker, G.B.; Mousseau, D.D. Profiles of β-amyloid peptides and key secretases in brain autopsy samples differ with sex and apoe ε4 status: impact for risk and progression of alzheimer disease. Neuroscience,  2018, 373, 20-36.
[http://dx.doi.org/10.1016/j.neuroscience.2018.01.005] [PMID:  29331531] 
[35] 
Nieznanska, H.; Bandyszewska, M.; Surewicz, K.; Zajkowski, T.; Surewicz, W.K.; Nieznanski, K. Identification of prion protein-derived peptides of potential use in Alzheimer’s disease therapy. Biochim. Biophys. Acta Mol. Basis Dis.,  2018, 1864(6 Pt A), 2143-2153.
[http://dx.doi.org/10.1016/j.bbadis.2018.03.023] [PMID:  29604335] 
[36] 
Coitinho, A.S.; Freitas, A.R.; Lopes, M.H.; Hajj, G.N.; Roesler, R.; Walz, R.; Rossato, J.I.; Cammarota, M.; Izquierdo, I.; Martins, V.R.; Brentani, R.R. The interaction between prion protein and laminin modulates memory consolidation. Eur. J. Neurosci.,  2006, 24(11), 3255-3264.
[http://dx.doi.org/10.1111/j.1460-9568.2006.05156.x] [PMID:  17156386] 
[37] 
Piccardo, P.; King, D.; Brown, D.; Barron, R.M. Variable tau accumulation in murine models with abnormal prion protein deposits. J. Neurol. Sci.,  2017, 383, 142-150.
[http://dx.doi.org/10.1016/j.jns.2017.10.040] [PMID:  29246602] 
[38] 
Hurlimann, J.; Thorbecke, G.J.; Hochwald, G.M. The liver as the site of C-reactive protein formation. J. Exp. Med.,  1966, 123(2), 365-378.
[http://dx.doi.org/10.1084/jem.123.2.365] [PMID:  4379352] 
[39] 
Marnell, L.; Mold, C.; Du Clos, T.W. C-reactive protein: ligands, receptors and role in inflammation. Clin. Immunol.,  2005, 117(2), 104-111.
[http://dx.doi.org/10.1016/j.clim.2005.08.004] [PMID:  16214080] 
[40] 
Del Giudice, M.; Gangestad, S.W. Rethinking IL-6 and CRP: Why they are more than inflammatory biomarkers, and why it matters. Brain Behav. Immun.,  2018, 70, 61-75.
[http://dx.doi.org/10.1016/j.bbi.2018.02.013] [PMID:  29499302] 
[41] 
Kravitz, B.A.; Corrada, M.M.; Kawas, C.H. Elevated C-reactive protein levels are associated with prevalent dementia in the oldest-old. Alzheimers Dement.,  2009, 5(4), 318-323.
[http://dx.doi.org/10.1016/j.jalz.2009.04.1230] [PMID:  19560102] 
[42] 
Bi, B.T.; Lin, H.B.; Cheng, Y.F.; Zhou, H.; Lin, T.; Zhang, M.Z.; Li, T.J.; Xu, J.P. Promotion of β-amyloid production by C-reactive protein and its implications in the early pathogenesis of Alzheimer’s disease. Neurochem. Int.,  2012, 60(3), 257-266.
[http://dx.doi.org/10.1016/j.neuint.2011.12.007] [PMID:  22202667] 
[43] 
Yang, S.; Hilton, S.; Alves, J.N.; Saksida, L.M.; Bussey, T.; Matthews, R.T.; Kitagawa, H.; Spillantini, M.G.; Kwok, J.C.F.; Fawcett, J.W. Antibody recognizing 4-sulfated chondroitin sulfate proteoglycans restores memory in tauopathy-induced neurodegeneration. Neurobiol. Aging,  2017, 59, 197-209.
[http://dx.doi.org/10.1016/j.neurobiolaging.2017.08.002] [PMID:  28890301] 
[44] 
Wesén, E.; Gallud, A.; Paul, A.; Lindberg, D.J.; Malmberg, P.; Esbjörner, E.K. Cell surface proteoglycan-mediated uptake and accumulation of the Alzheimer’s disease peptide Aβ(1-42). Biochim. Biophys. Acta Biomembr.,  2018, 1860(11), 2204-2214.
[http://dx.doi.org/10.1016/j.bbamem.2018.08.010] [PMID:  30409516] 
[45] 
Richard, A.D.; Tian, X.L.; El-Saadi, M.W.; Lu, X.H. Erasure of striatal chondroitin sulfate proteoglycan-associated extracellular matrix rescues aging-dependent decline of motor learning. Neurobiol. Aging,  2018, 71, 61-71.
[http://dx.doi.org/10.1016/j.neurobiolaging.2018.07.008] [PMID:  30099347] 
[46] 
Yan, H.; Zhu, X.; Xie, J.; Zhao, Y.; Liu, X. β-amyloid increases neurocan expression through regulating Sox9 in astrocytes: A potential relationship between Sox9 and chondroitin sulfate proteoglycans in Alzheimer’s disease. Brain Res.,  2016, 1646, 377-383.
[http://dx.doi.org/10.1016/j.brainres.2016.06.010] [PMID:  27317830] 
[47] 
Rauch, U.; Feng, K.; Zhou, X.H. Neurocan: a brain chondroitin sulfate proteoglycan. Cell. Mol. Life Sci.,  2001, 58(12-13), 1842-1856.
[http://dx.doi.org/10.1007/PL00000822] [PMID:  11766883] 
[48] 
Hol, E.M.; Pekny, M. Glial fibrillary acidic protein (GFAP) and the astrocyte intermediate filament system in diseases of the central nervous system. Curr. Opin. Cell Biol.,  2015, 32, 121-130.
[http://dx.doi.org/10.1016/j.ceb.2015.02.004] [PMID:  25726916] 
[49] 
Yang, Z.; Wang, K.K. Glial fibrillary acidic protein: from intermediate filament assembly and gliosis to neurobiomarker. Trends Neurosci.,  2015, 38(6), 364-374.
[http://dx.doi.org/10.1016/j.tins.2015.04.003] [PMID:  25975510] 
[50] 
Kamphuis, W.; Middeldorp, J.; Kooijman, L.; Sluijs, J.A.; Kooi, E.J.; Moeton, M.; Freriks, M.; Mizee, M.R.; Hol, E.M. Glial fibrillary acidic protein isoform expression in plaque related astrogliosis in Alzheimer’s disease. Neurobiol. Aging,  2014, 35(3), 492-510.
[http://dx.doi.org/10.1016/j.neurobiolaging.2013.09.035] [PMID:  24269023] 
[51] 
Korolainen, M.A.; Auriola, S.; Nyman, T.A.; Alafuzoff, I.; Pirttilä, T. Proteomic analysis of glial fibrillary acidic protein in Alzheimer’s disease and aging brain. Neurobiol. Dis.,  2005, 20(3), 858-870.
[http://dx.doi.org/10.1016/j.nbd.2005.05.021] [PMID:  15979880] 
[52] 
Marinissen, M.J.; Gutkind, J.S. G-protein-coupled receptors and signaling networks: emerging paradigms. Trends Pharmacol. Sci.,  2001, 22(7), 368-376.
[http://dx.doi.org/10.1016/S0165-6147(00)01678-3] [PMID:  11431032] 
[53] 
Nishimoto, I.; Okamoto, T.; Matsuura, Y.; Takahashi, S.; Okamoto, T.; Murayama, Y.; Ogata, E. Alzheimer amyloid protein precursor complexes with brain GTP-binding protein G(o). Nature,  1993, 362(6415), 75-79.
[http://dx.doi.org/10.1038/362075a0] [PMID:  8446172] 
[54] 
Bignante, E.A.; Ponce, N.E.; Heredia, F.; Musso, J.; Krawczyk, M.C.; Millán, J.; Pigino, G.F.; Inestrosa, N.C.; Boccia, M.M.; Lorenzo, A. APP/Go protein Gβγ-complex signaling mediates Aβ degeneration and cognitive impairment in Alzheimer’s disease models. Neurobiol. Aging,  2018, 64, 44-57.
[http://dx.doi.org/10.1016/j.neurobiolaging.2017.12.013] [PMID:  29331876] 
[55] 
Brocker, C.; Thompson, D.; Matsumoto, A.; Nebert, D.W.; Vasiliou, V. Evolutionary divergence and functions of the human interleukin (IL) gene family. Hum. Genomics,  2010, 5(1), 30-55.
[http://dx.doi.org/10.1186/1479-7364-5-1-30] [PMID:  21106488] 
[56] 
Sheng, J.G.; Jones, R.A.; Zhou, X.Q.; McGinness, J.M.; Van Eldik, L.J.; Mrak, R.E.; Griffin, W.S. Interleukin-1 promotion of MAPK-p38 overexpression in experimental animals and in Alzheimer’s disease: potential significance for tau protein phosphorylation. Neurochem. Int.,  2001, 39(5-6), 341-348.
[http://dx.doi.org/10.1016/S0197-0186(01)00041-9] [PMID:  11578769] 
[57] 
Mrak, R.E.; Griffin, W.S. Interleukin-1, neuroinflammation, and Alzheimer’s disease. Neurobiol. Aging,  2001, 22(6), 903-908.
[http://dx.doi.org/10.1016/S0197-4580(01)00287-1] [PMID:  11754997] 
[58] 
Blum-Degen, D.; Müller, T.; Kuhn, W.; Gerlach, M.; Przuntek, H.; Riederer, P. Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer’s and de novo Parkinson’s disease patients. Neurosci. Lett.,  1995, 202(1-2), 17-20.
[http://dx.doi.org/10.1016/0304-3940(95)12192-7] [PMID:  8787820] 
[59] 
Bauer, J.; Strauss, S.; Schreiter-Gasser, U.; Ganter, U.; Schlegel, P.; Witt, I.; Yolk, B.; Berger, M. Interleukin-6 and alpha-2-macroglobulin indicate an acute-phase state in Alzheimer’s disease cortices. FEBS Lett.,  1991, 285(1), 111-114.
[http://dx.doi.org/10.1016/0014-5793(91)80737-N] [PMID:  1712317] 
[60] 
Bossù, P.; Ciaramella, A.; Salani, F.; Vanni, D.; Palladino, I.; Caltagirone, C.; Scapigliati, G. Interleukin-18, from neuroinflammation to Alzheimer’s disease. Curr. Pharm. Des.,  2010, 16(38), 4213-4224.
[http://dx.doi.org/10.2174/138161210794519147] [PMID:  21184660] 
[61] 
Kilic, U.; Elibol, B.; Uysal, O.; Kilic, E.; Yulug, B.; Sayin Sakul, A.; Babacan Yildiz, G. Specific alterations in the circulating levels of the SIRT1, TLR4, and IL7 proteins in patients with dementia. Exp. Gerontol.,  2018, 111, 203-209.
[http://dx.doi.org/10.1016/j.exger.2018.07.018] [PMID:  30071285] 
[62] 
Entrez Gene: CUTA1 copper-binding protein CutA [Chlamydomonas
reinhardtii]. https://www.ncbi.nlm.nih.gov/gene/?term=A8I832 (accessed 8 April 2019)
[63] 
Arnesano, F.; Banci, L.; Benvenuti, M.; Bertini, I.; Calderone, V.; Mangani, S.; Viezzoli, M.S. The evolutionarily conserved trimeric structure of CutA1 proteins suggests a role in signal transduction. J. Biol. Chem.,  2003, 278(46), 45999-46006.
[http://dx.doi.org/10.1074/jbc.M304398200] [PMID:  12949080] 
[64] 
Zhao, Y.; Wang, Y.; Hu, J.; Zhang, X.; Zhang, Y.W. CutA divalent cation tolerance homolog (Escherichia coli) (CUTA) regulates β-cleavage of β-amyloid precursor protein (APP) through interacting with β-site APP cleaving protein 1 (BACE1). J. Biol. Chem.,  2012, 287(14), 11141-11150.
[http://dx.doi.org/10.1074/jbc.M111.330209] [PMID:  22351782] 
[65] 
Hou, P.; Liu, G.; Zhao, Y.; Shi, Z.; Zheng, Q.; Bu, G.; Xu, H.; Zhang, Y.W. Role of copper and the copper-related protein CUTA in mediating APP processing and Aβ generation. Neurobiol. Aging,  2015, 36(3), 1310-1315.
[http://dx.doi.org/10.1016/j.neurobiolaging.2014.12.005] [PMID:  25557959] 
[66] 
Kitazawa, M.; Cheng, D.; Laferla, F.M. Chronic copper exposure exacerbates both amyloid and tau pathology and selectively dysregulates cdk5 in a mouse model of AD. J. Neurochem.,  2009, 108(6), 1550-1560.
[http://dx.doi.org/10.1111/j.1471-4159.2009.05901.x] [PMID:  19183260] 
[67] 
Entrez Gene: SLC25A37 solute carrier family 25 member 37
[Homo sapiens (human)]. https://www.ncbi.nlm.nih.gov/gene/51312 (accessed 8 April 2019)
[68] 
Hentze, M.W.; Muckenthaler, M.U.; Galy, B.; Camaschella, C. Two to tango: regulation of Mammalian iron metabolism. Cell,  2010, 142(1), 24-38.
[http://dx.doi.org/10.1016/j.cell.2010.06.028] [PMID:  20603012] 
[69] 
Hanmanthraya, B.; Byrne, A. Haemochromatosis and dementia: cause or contributor. Prog. Neurol. Psychiatry,  2015, 19, 5-8.
[http://dx.doi.org/10.1002/pnp.378] 
[70] 
Huang, J.; Chen, S.; Hu, L.; Niu, H.; Sun, Q.; Li, W.; Tan, G.; Li, J.; Jin, L.; Lyu, J.; Zhou, H. Mitoferrin-1 is involved in the progression of Alzheimer’s Disease through targeting mitochondrial iron metabolism in a Caenorhabditis elegans Model of Alzheimer’s Disease. Neuroscience,  2018, 385, 90-101.
[http://dx.doi.org/10.1016/j.neuroscience.2018.06.011] [PMID:  29908215] 
[71] 
Carr, M.W.; Roth, S.J.; Luther, E.; Rose, S.S.; Springer, T.A. Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant. Proc. Natl. Acad. Sci. USA,  1994, 91(9), 3652-3656.
[http://dx.doi.org/10.1073/pnas.91.9.3652] [PMID:  8170963] 
[72] 
Xu, L.L.; Warren, M.K.; Rose, W.L.; Gong, W.; Wang, J.M. Human recombinant monocyte chemotactic protein and other C-C chemokines bind and induce directional migration of dendritic cells in vitro. J. Leukoc. Biol.,  1996, 60(3), 365-371.
[http://dx.doi.org/10.1002/jlb.60.3.365] [PMID:  8830793] 
[73] 
Deshmane, S.L.; Kremlev, S.; Amini, S.; Sawaya, B.E. Monocyte chemoattractant protein-1 (MCP-1): an overview. J. Interferon Cytokine Res.,  2009, 29(6), 313-326.
[http://dx.doi.org/10.1089/jir.2008.0027] [PMID:  19441883] 
[74] 
Muessel, M.J.; Berman, N.E.; Klein, R.M. Early and specific expression of monocyte chemoattractant protein-1 in the thalamus induced by cortical injury. Brain Res.,  2000, 870(1-2), 211-221.
[http://dx.doi.org/10.1016/S0006-8993(00)02450-1] [PMID:  10869521] 
[75] 
Kalehua, A.N.; Nagel, J.E.; Whelchel, L.M.; Gides, J.J.; Pyle, R.S.; Smith, R.J.; Kusiak, J.W.; Taub, D.D. Monocyte chemoattractant protein-1 and macrophage inflammatory protein-2 are involved in both excitotoxin-induced neurodegeneration and regeneration. Exp. Cell Res.,  2004, 297(1), 197-211.
[http://dx.doi.org/10.1016/j.yexcr.2004.02.031] [PMID:  15194436] 
[76] 
Persidsky, Y.; Ghorpade, A.; Rasmussen, J.; Limoges, J.; Liu, X.J.; Stins, M.; Fiala, M.; Way, D.; Kim, K.S.; Witte, M.H.; Weinand, M.; Carhart, L.; Gendelman, H.E. Microglial and astrocyte chemokines regulate monocyte migration through the blood-brain barrier in human immunodeficiency virus-1 encephalitis. Am. J. Pathol.,  1999, 155(5), 1599-1611.
[http://dx.doi.org/10.1016/S0002-9440(10)65476-4] [PMID:  10550317] 
[77] 
Coughlan, C.M.; McManus, C.M.; Sharron, M.; Gao, Z.; Murphy, D.; Jaffer, S.; Choe, W.; Chen, W.; Hesselgesser, J.; Gaylord, H.; Kalyuzhny, A.; Lee, V.M.; Wolf, B.; Doms, R.W.; Kolson, D.L. Expression of multiple functional chemokine receptors and monocyte chemoattractant protein-1 in human neurons. Neuroscience,  2000, 97(3), 591-600.
[http://dx.doi.org/10.1016/S0306-4522(00)00024-5] [PMID:  10828541] 
[78] 
Muessel, M.J.; Klein, R.M.; Wilson, A.M.; Berman, N.E. Ablation of the chemokine monocyte chemoattractant protein-1 delays retrograde neuronal degeneration, attenuates microglial activation, and alters expression of cell death molecules. Brain Res. Mol. Brain Res.,  2002, 103(1-2), 12-27.
[http://dx.doi.org/10.1016/S0169-328X(02)00158-4] [PMID:  12106688] 
[79] 
Gewurz, H.; Zhang, X.H.; Lint, T.F. Structure and function of the pentraxins. Curr. Opin. Immunol.,  1995, 7(1), 54-64.
[http://dx.doi.org/10.1016/0952-7915(95)80029-8] [PMID:  7772283] 
[80] 
Omeis, I.A.; Hsu, Y.C.; Perin, M.S. Mouse and human neuronal pentraxin 1 (NPTX1): conservation, genomic structure, and chromosomal localization. Genomics,  1996, 36(3), 543-545.
[http://dx.doi.org/10.1006/geno.1996.0503] [PMID:  8884281] 
[81] 
McGeer, E.G.; Yasojima, K.; Schwab, C.; McGeer, P.L. The pentraxins: possible role in Alzheimer’s disease and other innate inflammatory diseases. Neurobiol. Aging,  2001, 22(6), 843-848.
[http://dx.doi.org/10.1016/S0197-4580(01)00288-3] [PMID:  11754991] 
[82] 
Farhy-Tselnicker, I.; van Casteren, A.C.M.; Lee, A.; Chang, V.T.; Aricescu, A.R.; Allen, N.J. Astrocyte-secreted glypican 4 regulates release of neuronal pentraxin 1 from axons to induce functional synapse formation. Neuron,  2017, 96(2), 428-445.e13.
[http://dx.doi.org/10.1016/j.neuron.2017.09.053] [PMID:  29024665] 
[83] 
Ma, Q.L.; Teng, E.; Zuo, X.; Jones, M.; Teter, B.; Zhao, E.Y.; Zhu, C.; Bilousova, T.; Gylys, K.H.; Apostolova, L.G.; LaDu, M.J.; Hossain, M.A.; Frautschy, S.A.; Cole, G.M. Neuronal pentraxin 1: A synaptic-derived plasma biomarker in Alzheimer’s disease. Neurobiol. Dis.,  2018, 114, 120-128.
[http://dx.doi.org/10.1016/j.nbd.2018.02.014] [PMID:  29501530] 
[84] 
Swanson, A.; Willette, A.A. Alzheimer’s Disease Neuroimaging Initiative. Neuronal Pentraxin 2 predicts medial temporal atrophy and memory decline across the Alzheimer’s disease spectrum. Brain Behav. Immun.,  2016, 58, 201-208.
[http://dx.doi.org/10.1016/j.bbi.2016.07.148] [PMID:  27444967] 
[85] 
Bilousova, T.; Taylor, K.; Emirzian, A.; Gylys, R.; Frautschy, S.A.; Cole, G.M.; Teng, E. Parallel age-associated changes in brain and plasma neuronal pentraxin receptor levels in a transgenic APP/PS1 rat model of Alzheimer’s disease. Neurobiol. Dis.,  2015, 74, 32-40.
[http://dx.doi.org/10.1016/j.nbd.2014.11.006] [PMID:  25449907] 
[86] 
Duong, T.; Acton, P.J.; Johnson, R.A. The in vitro neuronal toxicity of pentraxins associated with Alzheimer’s disease brain lesions. Brain Res.,  1998, 813(2), 303-312.
[http://dx.doi.org/10.1016/S0006-8993(98)00966-4] [PMID:  9838173] 
[87] 
Entrez Gene: UBQLN1 ubiquilin 1 [Homo sapiens (human)]. https://www.ncbi.nlm.nih.gov/gene/?term=29979  (accessed 8 April 2019)
[88] 
El Ayadi, A.; Stieren, E.S.; Barral, J.M.; Boehning, D. Ubiquilin-1 and protein quality control in Alzheimer disease. Prion,  2013, 7(2), 164-169.
[http://dx.doi.org/10.4161/pri.23711] [PMID:  23360761] 
[89] 
Jantrapirom, S.; Lo Piccolo, L.; Yoshida, H.; Yamaguchi, M. A new Drosophila model of Ubiquilin knockdown shows the effect of impaired proteostasis on locomotive and learning abilities. Exp. Cell Res.,  2018, 362(2), 461-471.
[http://dx.doi.org/10.1016/j.yexcr.2017.12.010] [PMID:  29247619] 
[90] 
Natunen, T.; Takalo, M.; Kemppainen, S.; Leskelä, S.; Marttinen, M.; Kurkinen, K.M.A.; Pursiheimo, J.P.; Sarajärvi, T.; Viswanathan, J.; Gabbouj, S.; Solje, E.; Tahvanainen, E.; Pirttimäki, T.; Kurki, M.; Paananen, J.; Rauramaa, T.; Miettinen, P.; Mäkinen, P.; Leinonen, V.; Soininen, H.; Airenne, K.; Tanzi, R.E.; Tanila, H.; Haapasalo, A.; Hiltunen, M. Relationship between ubiquilin-1 and BACE1 in human Alzheimer’s disease and APdE9 transgenic mouse brain and cell-based models. Neurobiol. Dis.,  2016, 85, 187-205.
[http://dx.doi.org/10.1016/j.nbd.2015.11.005] [PMID:  26563932] 
[91] 
Viswanathan, J.; Haapasalo, A.; Böttcher, C.; Miettinen, R.; Kurkinen, K.M.; Lu, A.; Thomas, A.; Maynard, C.J.; Romano, D.; Hyman, B.T.; Berezovska, O.; Bertram, L.; Soininen, H.; Dantuma, N.P.; Tanzi, R.E.; Hiltunen, M. Alzheimer’s disease-associated ubiquilin-1 regulates presenilin-1 accumulation and aggresome formation. Traffic,  2011, 12(3), 330-348.
[http://dx.doi.org/10.1111/j.1600-0854.2010.01149.x] [PMID:  21143716] 
[92] 
Sherrington, R.; Rogaev, E.I.; Liang, Y.; Rogaeva, E.A.; Levesque, G.; Ikeda, M.; Chi, H.; Lin, C.; Li, G.; Holman, K.; Tsuda, T.; Mar, L.; Foncin, J.F.; Bruni, A.C.; Montesi, M.P.; Sorbi, S.; Rainero, I.; Pinessi, L.; Nee, L.; Chumakov, I.; Pollen, D.; Brookes, A.; Sanseau, P.; Polinsky, R.J.; Wasco, W.; Da Silva, H.A.; Haines, J.L.; Perkicak-Vance, M.A.; Tanzi, R.E.; Roses, A.D.; Fraser, P.E.; Rommens, J.M.; St George-Hyslop, P.H. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature,  1995, 375(6534), 754-760.
[http://dx.doi.org/10.1038/375754a0] [PMID:  7596406] 
[93] 
Levy-Lahad, E.; Wasco, W.; Poorkaj, P.; Romano, D.M.; Oshima, J.; Pettingell, W.H.; Yu, C.E.; Jondro, P.D.; Schmidt, S.D.; Wang, K. Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science,  1995, 269(5226), 973-977.
[http://dx.doi.org/10.1126/science.7638622] [PMID:  7638622] 
[94] 
Duncan, R.S.; Song, B.; Koulen, P. Presenilins as Drug Targets for Alzheimer’s Disease-Recent Insights from Cell Biology and Electrophysiology as Novel Opportunities in Drug Development. Int. J. Mol. Sci.,  2018, 19(6), E1621.
[http://dx.doi.org/10.3390/ijms19061621] [PMID:  29857474] 
[95] 
Ebke, A.; Luebbers, T.; Fukumori, A.; Shirotani, K.; Haass, C.; Baumann, K.; Steiner, H. Novel γ-secretase enzyme modulators directly target presenilin protein. J. Biol. Chem.,  2011, 286(43), 37181-37186.
[http://dx.doi.org/10.1074/jbc.C111.276972] [PMID:  21896486] 
[96] 
Iwatsubo, T. Aβ42, Presenilins, and Alzheimer’s Disease. Neurobiol. Aging,  1998, 19, 11-13.
[http://dx.doi.org/10.1016/S0197-4580(98)00027-X] 
[97] 
Entrez Gene: SORL1 sortilin related receptor 1 [Homo sapiens
(human)]. https://www.ncbi.nlm.nih.gov/gene/6653 (accessed 8
April 2019)
[98] 
Spoelgen, R.; Adams, K.W.; Koker, M.; Thomas, A.V.; Andersen, O.M.; Hallett, P.J.; Bercury, K.K.; Joyner, D.F.; Deng, M.; Stoothoff, W.H.; Strickland, D.K.; Willnow, T.E.; Hyman, B.T. Interaction of the apolipoprotein E receptors low density lipoprotein receptor-related protein and sorLA/LR11. Neuroscience,  2009, 158(4), 1460-1468.
[http://dx.doi.org/10.1016/j.neuroscience.2008.10.061] [PMID:  19047013] 
[99] 
Andersen, O.M.; Schmidt, V.; Spoelgen, R.; Gliemann, J.; Behlke, J.; Galatis, D.; McKinstry, W.J.; Parker, M.W.; Masters, C.L.; Hyman, B.T.; Cappai, R.; Willnow, T.E. Molecular dissection of the interaction between amyloid precursor protein and its neuronal trafficking receptor SorLA/LR11. Biochemistry,  2006, 45(8), 2618-2628.
[http://dx.doi.org/10.1021/bi052120v] [PMID:  16489755] 
[100] 
Hartl, D.; Nebrich, G.; Klein, O.; Stephanowitz, H.; Krause, E.; Rohe, M. SORLA regulates calpain-dependent degradation of synapsin. Alzheimers Dement.,  2016, 12(9), 952-963.
[http://dx.doi.org/10.1016/j.jalz.2016.02.008] [PMID:  27021222] 
[101] 
Gill, R.L., Jr; Wang, X.; Tian, F. A membrane proximal helix in the cytosolic domain of the human APP interacting protein LR11/SorLA deforms liposomes. Biochim. Biophys. Acta,  2015, 1848(1 Pt B), 323-328.
[http://dx.doi.org/10.1016/j.bbamem.2014.05.020] [PMID:  24866012] 
[102] 
Motoi, Y.; Aizawa, T.; Haga, S.; Nakamura, S.; Namba, Y.; Ikeda, K. Neuronal localization of a novel mosaic apolipoprotein E receptor, LR11, in rat and human brain. Brain Res.,  1999, 833(2), 209-215.
[http://dx.doi.org/10.1016/S0006-8993(99)01542-5] [PMID:  10375696] 
[103] 
Entrez Gene: SNCA synuclein alpha [Homo sapiens (human)]. https://www.ncbi.nlm.nih.gov/gene/?term=6622 (accessed 8 April 2019)
[104] 
Wong, Y.C.; Krainc, D. α-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies. Nat. Med.,  2017, 23(2), 1-13.
[http://dx.doi.org/10.1038/nm.4269] [PMID:  28170377] 
[105] 
Fang, F.; Yang, W.; Florio, J.B.; Rockenstein, E.; Spencer, B.; Orain, X.M.; Dong, S.X.; Li, H.; Chen, X.; Sung, K.; Rissman, R.A.; Masliah, E.; Ding, J.; Wu, C. Synuclein impairs trafficking and signaling of BDNF in a mouse model of Parkinson’s disease. Sci. Rep.,  2017, 7(1), 3868.
[http://dx.doi.org/10.1038/s41598-017-04232-4] [PMID:  28634349] 
[106] 
Colom-Cadena, M.; Pegueroles, J.; Herrmann, A.G.; Henstridge, C.M.; Muñoz, L.; Querol-Vilaseca, M.; Martín-Paniello, C.S.; Luque-Cabecerans, J.; Clarimon, J.; Belbin, O.; Núñez-Llaves, R.; Blesa, R.; Smith, C.; McKenzie, C.A.; Frosch, M.P.; Roe, A.; Fortea, J.; Andilla, J.; Loza-Alvarez, P.; Gelpi, E.; Hyman, B.T.; Spires-Jones, T.L.; Lleó, A. Synaptic phosphorylated α-synuclein in dementia with Lewy bodies. Brain,  2017, 140(12), 3204-3214.
[http://dx.doi.org/10.1093/brain/awx275] [PMID:  29177427] 
[107] 
Vergallo, A.; Bun, R.S.; Toschi, N.; Baldacci, F.; Zetterberg, H.; Blennow, K.; Cavedo, E.; Lamari, F.; Habert, M.O.; Dubois, B.; Floris, R.; Garaci, F.; Lista, S.; Hampel, H. INSIGHT-preAD study group. Alzheimer Precision Medicine Initiative (APMI). Association of cerebrospinal fluid α-synuclein with total and phospho-tau181 protein concentrations and brain amyloid load in cognitively normal subjective memory complainers stratified by Alzheimer’s disease biomarkers. Alzheimers Dement.,  2018, 14(12), 1623-1631.
[http://dx.doi.org/10.1016/j.jalz.2018.06.3053] [PMID:  30055132] 
[108] 
Shi, M.; Tang, L.; Toledo, J.B.; Ginghina, C.; Wang, H.; Aro, P.; Jensen, P.H.; Weintraub, D.; Chen-Plotkin, A.S.; Irwin, D.J.; Grossman, M.; McCluskey, L.; Elman, L.B.; Wolk, D.A.; Lee, E.B.; Shaw, L.M.; Trojanowski, J.Q.; Zhang, J. Cerebrospinal fluid α-synuclein contributes to the differential diagnosis of Alzheimer’s disease. Alzheimers Dement.,  2018, 14(8), 1052-1062.
[http://dx.doi.org/10.1016/j.jalz.2018.02.015] [PMID:  29604263] 
[109] 
Slaets, S.; Vanmechelen, E.; Le Bastard, N.; Decraemer, H.; Vandijck, M.; Martin, J.J.; De Deyn, P.P.; Engelborghs, S. Increased CSF α-synuclein levels in Alzheimer’s disease: correlation with tau levels. Alzheimers Dement.,  2014, 10(5)(Suppl.), S290-S298.
[http://dx.doi.org/10.1016/j.jalz.2013.10.004
          ] [PMID:  24439167] 
[110] 
Gaspar, R.; Pallbo, J.; Weininger, U.; Linse, S.; Sparr, E. Ganglioside lipids accelerate α-synuclein amyloid formation. Biochim. Biophys. Acta. Proteins Proteomics,  2018, 1866, 1062-1072.
[http://dx.doi.org/10.1016/j.bbapap.2018.07.004] [PMID:  30077783] 
[111] 
Whiten, D.R.; Cox, D.; Horrocks, M.H.; Taylor, C.G.; De, S.; Flagmeier, P.; Tosatto, L.; Kumita, J.R.; Ecroyd, H.; Dobson, C.M.; Klenerman, D.; Wilson, M.R. Single-molecule characterization of the interactions between extracellular chaperones and toxic α-synuclein oligomers. Cell Rep.,  2018, 23(12), 3492-3500.
[http://dx.doi.org/10.1016/j.celrep.2018.05.074] [PMID:  29924993] 
[112] 
Bar, R.; Boehm-Cagan, A.; Luz, I.; Kleper-Wall, Y.; Michaelson, D.M. The effects of apolipoprotein E genotype, α-synuclein deficiency, and sex on brain synaptic and Alzheimer’s disease-related pathology. Alzheimers Dement. (Amst.),  2017, 10, 1-11.
[http://dx.doi.org/10.1016/j.dadm.2017.08.003] [PMID:  29159264] 
[113] 
Castillo-Carranza, D.L.; Guerrero-Muñoz, M.J.; Sengupta, U.; Gerson, J.E.; Kayed, R. α-Synuclein oligomers induce a unique toxic tau strain. Biol. Psychiatry,  2018, 84(7), 499-508.
[http://dx.doi.org/10.1016/j.biopsych.2017.12.018] [PMID:  29478699] 
[114] 
Goedert, M.; Spillantini, M.G.; Jakes, R.; Rutherford, D.; Crowther, R.A. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron,  1989, 3(4), 519-526.
[http://dx.doi.org/10.1016/0896-6273(89)90210-9] [PMID:  2484340] 
[115] 
Goedert, M.; Wischik, C.M.; Crowther, R.A.; Walker, J.E.; Klug, A. Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc. Natl. Acad. Sci. USA,  1988, 85(11), 4051-4055.
[http://dx.doi.org/10.1073/pnas.85.11.4051] [PMID:  3131773] 
[116] 
Vlassenko, A.G.; Gordon, B.A.; Goyal, M.S.; Su, Y.; Blazey, T.M.; Durbin, T.J.; Couture, L.E.; Christensen, J.J.; Jafri, H.; Morris, J.C.; Raichle, M.E.; Benzinger, T.L. Aerobic glycolysis and tau deposition in preclinical Alzheimer’s disease. Neurobiol. Aging,  2018, 67, 95-98.
[http://dx.doi.org/10.1016/j.neurobiolaging.2018.03.014] [PMID:  29655050] 
[117] 
Shentu, Y.P.; Huo, Y.; Feng, X.L.; Gilbert, J.; Zhang, Q.; Liuyang, Z.Y.; Wang, X.L.; Wang, G.; Zhou, H.; Wang, X.C.; Wang, J.Z.; Lu, Y.M.; Westermarck, J.; Man, H.Y.; Liu, R. CIP2A causes tau/app phosphorylation, synaptopathy, and memory deficits in alzheimer’s disease. Cell Rep.,  2018, 24(3), 713-723.
[http://dx.doi.org/10.1016/j.celrep.2018.06.009] [PMID:  30021167] 
[118] 
Miron, J.; Picard, C.; Nilsson, N.; Frappier, J.; Dea, D.; Théroux, L.; Poirier, J. alzheimer’s disease neuroimaging initiative; united kingdom brain expression consortium. cdk5rap2 gene and tau pathophysiology in late-onset sporadic Alzheimer’s disease. Alzheimers Dement.,  2018, 14(6), 787-796.
[http://dx.doi.org/10.1016/j.jalz.2017.12.004] [PMID:  29360470] 
[119] 
Parbo, P.; Ismail, R.; Sommerauer, M.; Stokholm, M.G.; Hansen, A.K.; Hansen, K.V.; Amidi, A.; Schaldemose, J.L.; Gottrup, H.; Brændgaard, H.; Eskildsen, S.F.; Borghammer, P.; Hinz, R.; Aanerud, J.; Brooks, D.J. Does inflammation precede tau aggregation in early Alzheimer’s disease? A PET study. Neurobiol. Dis.,  2018, 117, 211-216.
[http://dx.doi.org/10.1016/j.nbd.2018.06.004] [PMID:  29902557] 
[120] 
Alam, J.; Sharma, L. Potential enzymatic targets in Alzheimer’s: A comprehensive review. Curr. Drug Targets,  2019, 20(3), 316-339.
[http://dx.doi.org/10.2174/1389450119666180820104723] [PMID:  30124150] 
[121] 
Eftekharzadeh, B.; Daigle, J.G.; Kapinos, L.E.; Coyne, A.; Schiantarelli, J.; Carlomagno, Y.; Cook, C.; Miller, S.J.; Dujardin, S.; Amaral, A.S.; Grima, J.C.; Bennett, R.E.; Tepper, K.; DeTure, M.; Vanderburg, C.R.; Corjuc, B.T.; DeVos, S.L.; Gonzalez, J.A.; Chew, J.; Vidensky, S.; Gage, F.H.; Mertens, J.; Troncoso, J.; Mandelkow, E.; Salvatella, X.; Lim, R.Y.H.; Petrucelli, L.; Wegmann, S.; Rothstein, J.D.; Hyman, B.T. Tau protein disrupts nucleocytoplasmic transport in Alzheimer’s Disease. Neuron,  2019, 101(2), 349.
[http://dx.doi.org/10.1016/j.neuron.2018.12.031] [PMID:  30653936] 
[122] 
Mielke, M.M.; Hagen, C.E.; Xu, J.; Chai, X.; Vemuri, P.; Lowe, V.J.; Airey, D.C.; Knopman, D.S.; Roberts, R.O.; Machulda, M.M.; Jack, C.R., Jr; Petersen, R.C.; Dage, J.L. Plasma phospho-tau181 increases with Alzheimer’s disease clinical severity and is associated with tau- and amyloid-positron emission tomography. Alzheimers Dement.,  2018, 14(8), 989-997.
[http://dx.doi.org/10.1016/j.jalz.2018.02.013] [PMID:  29626426] 
[123] 
Pekeles, H.; Qureshi, H.Y.; Paudel, H.K.; Schipper, H.M.; Gornistky, M.; Chertkow, H. Development and validation of a salivary tau biomarker in Alzheimer’s disease. Alzheimers Dement. (Amst.),  2018, 11, 53-60.
[http://dx.doi.org/10.1016/j.dadm.2018.03.003] [PMID:  30623019] 
[124] 
Babini, E.; Bertini, I.; Capozzi, F.; Chirivino, E.; Luchinat, C. A structural and dynamic characterization of the EF-hand protein CLSP. Structure,  2006, 14(6), 1029-1038.
[http://dx.doi.org/10.1016/j.str.2006.04.004] [PMID:  16765896] 
[125] 
Matsuoka, M. Protective effects of Humanin and calmodulin-like skin protein in Alzheimer’s disease and broad range of abnormalities. Mol. Neurobiol.,  2015, 51(3), 1232-1239.
[http://dx.doi.org/10.1007/s12035-014-8799-1] [PMID:  24969584] 
[126] 
Hashimoto, Y.; Kurita, M.; Aiso, S.; Nishimoto, I.; Matsuoka, M. Humanin inhibits neuronal cell death by interacting with a cytokine receptor complex or complexes involving CNTF receptor alpha/WSX-1/gp130. Mol. Biol. Cell,  2009, 20(12), 2864-2873.
[http://dx.doi.org/10.1091/mbc.e09-02-0168] [PMID:  19386761] 
[127] 
Hashimoto, Y.; Kurita, M.; Matsuoka, M. Identification of soluble WSX-1 not as a dominant-negative but as an alternative functional subunit of a receptor for an anti-Alzheimer’s disease rescue factor Humanin. Biochem. Biophys. Res. Commun.,  2009, 389(1), 95-99.
[http://dx.doi.org/10.1016/j.bbrc.2009.08.095] [PMID:  19703422] 
[128] 
Kusakari, S.; Nawa, M.; Sudo, K.; Matsuoka, M. Calmodulin-like skin protein protects against spatial learning impairment in a mouse model of Alzheimer disease. J. Neurochem.,  2018, 144(2), 218-233.
[http://dx.doi.org/10.1111/jnc.14258] [PMID:  29164613] 
[129] 
Hashimoto, Y.; Umahara, T.; Hanyu, H.; Iwamoto, T.; Matsuoka, M. Calmodulin-like skin protein is downregulated in human cerebrospinal fluids of Alzheimer’s disease patients with apolipoprotein E4; a pilot study using postmortem samples. Neurol. Res.,  2017, 39(9), 767-772.
[http://dx.doi.org/10.1080/01616412.2017.1335458] [PMID:  28592211] 
[130] 
Ritossa, F.M. A New puffing pattern induced by temperature shock and dnp in Drosophila. Cell. Mol. Life Sci.,  1962, 18, 571-573.
[http://dx.doi.org/10.1007/BF02172188] 
[131] 
Matz, J.M.; Blake, M.J.; Tatelman, H.M.; Lavoi, K.P.; Holbrook, N.J. Characterization and regulation of cold-induced heat shock protein expression in mouse brown adipose tissue. Am. J. Physiol.,  1995, 269(1 Pt 2), R38-R47.
[PMID: 7631901] 
[132] 
Cao, Y.; Ohwatari, N.; Matsumoto, T.; Kosaka, M.; Ohtsuru, A.; Yamashita, S. TGF-beta1 mediates 70-kDa heat shock protein induction due to ultraviolet irradiation in human skin fibroblasts. Pflugers Arch.,  1999, 438(3), 239-244.
[http://dx.doi.org/10.1007/s004240050905] [PMID:  10398851] 
[133] 
Laplante, A.F.; Moulin, V.; Auger, F.A.; Landry, J.; Li, H.; Morrow, G.; Tanguay, R.M.; Germain, L. Expression of heat shock proteins in mouse skin during wound healing. J. Histochem. Cytochem.,  1998, 46(11), 1291-1301.
[http://dx.doi.org/10.1177/002215549804601109] [PMID:  9774628] 
[134] 
Abdul, H.M.; Calabrese, V.; Calvani, M.; Butterfield, D.A. Acetyl-L-carnitine-induced up-regulation of heat shock proteins protects cortical neurons against amyloid-beta peptide 1-42-mediated oxidative stress and neurotoxicity: implications for Alzheimer’s disease. J. Neurosci. Res.,  2006, 84(2), 398-408.
[http://dx.doi.org/10.1002/jnr.20877] [PMID:  16634066] 
[135] 
Hensley, K.; Hall, N.; Subramaniam, R.; Cole, P.; Harris, M.; Aksenov, M.; Aksenova, M.; Gabbita, S.P.; Wu, J.F.; Carney, J.M. Brain regional correspondence between Alzheimer’s disease histopathology and biomarkers of protein oxidation. J. Neurochem.,  1995, 65(5), 2146-2156.
[http://dx.doi.org/10.1046/j.1471-4159.1995.65052146.x] [PMID:  7595501] 
[136] 
Clarimón, J.; Bertranpetit, J.; Boada, M.; Tàrraga, L.; Comas, D. HSP70-2 (HSPA1B) is associated with noncognitive symptoms in late-onset Alzheimer’s disease. J. Geriatr. Psychiatry Neurol.,  2003, 16(3), 146-150.
[http://dx.doi.org/10.1177/0891988703256051] [PMID:  12967056] 
[137] 
Renkawek, K.; Bosman, G.J.; de Jong, W.W. Expression of small heat-shock protein hsp 27 in reactive gliosis in Alzheimer disease and other types of dementia. Acta Neuropathol.,  1994, 87(5), 511-519.
[http://dx.doi.org/10.1007/BF00294178] [PMID:  8059604] 
[138] 
Renkawek, K.; Bosman, G.J.; Gaestel, M. Increased expression of heat-shock protein 27 kDa in Alzheimer disease: a preliminary study. Neuroreport,  1993, 5(1), 14-16.
[http://dx.doi.org/10.1097/00001756-199310000-00003] [PMID:  8280851] 
[139] 
Jiang, Y.Q.; Wang, X.L.; Cao, X.H.; Ye, Z.Y.; Li, L.; Cai, W.Q. Increased heat shock transcription factor 1 in the cerebellum reverses the deficiency of Purkinje cells in Alzheimer’s disease. Brain Res.,  2013, 1519, 105-111.
[http://dx.doi.org/10.1016/j.brainres.2013.04.059] [PMID:  23665061] 
[140] 
Arimura, N.; Menager, C.; Fukata, Y.; Kaibuchi, K. Role of CRMP-2 in neuronal polarity. J. Neurobiol.,  2004, 58(1), 34-47.
[http://dx.doi.org/10.1002/neu.10269] [PMID:  14598368] 
[141] 
Cole, A.R.; Noble, W.; van Aalten, L.; Plattner, F.; Meimaridou, R.; Hogan, D.; Taylor, M.; LaFrancois, J.; Gunn-Moore, F.; Verkhratsky, A.; Oddo, S.; LaFerla, F.; Giese, K.P.; Dineley, K.T.; Duff, K.; Richardson, J.C.; Yan, S.D.; Hanger, D.P.; Allan, S.M.; Sutherland, C. Collapsin response mediator protein-2 hyperphosphorylation is an early event in Alzheimer’s disease progression. J. Neurochem.,  2007, 103(3), 1132-1144.
[http://dx.doi.org/10.1111/j.1471-4159.2007.04829.x] [PMID:  17683481] 
[142] 
Entrez Gene: LRP1 LDL receptor related protein 1 [Homo sapiens
(human)] . https://www.ncbi.nlm.nih.gov/gene/4035 (accessed 8 April 2019.
[143] 
Shibata, M.; Yamada, S.; Kumar, S.R.; Calero, M.; Bading, J.; Frangione, B.; Holtzman, D.M.; Miller, C.A.; Strickland, D.K.; Ghiso, J.; Zlokovic, B.V. Clearance of Alzheimer’s amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J. Clin. Invest.,  2000, 106(12), 1489-1499.
[http://dx.doi.org/10.1172/JCI10498] [PMID:  11120756] 
[144] 
Liu, Q.; Zerbinatti, C.V.; Zhang, J.; Hoe, H.S.; Wang, B.; Cole, S.L.; Herz, J.; Muglia, L.; Bu, G. Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1. Neuron,  2007, 56(1), 66-78.
[http://dx.doi.org/10.1016/j.neuron.2007.08.008] [PMID:  17920016] 
[145] 
Van Uden, E.; Carlson, G.; St George-Hyslop, P.; Westaway, D.; Orlando, R.; Mallory, M.; Rockenstein, E.; Masliah, E. Aberrant presenilin-1 expression downregulates LDL receptor-related protein (LRP): is LRP central to Alzheimer’s disease pathogenesis? Mol. Cell. Neurosci.,  1999, 14(2), 129-140.
[http://dx.doi.org/10.1006/mcne.1999.0772] [PMID:  10479411] 
[146] 
Owen, J.B.; Sultana, R.; Aluise, C.D.; Erickson, M.A.; Price, T.O.; Bu, G.; Banks, W.A.; Butterfield, D.A. Oxidative modification to LDL receptor-related protein 1 in hippocampus from subjects with Alzheimer disease: implications for Aβ accumulation in AD brain. Free Radic. Biol. Med.,  2010, 49(11), 1798-1803.
[http://dx.doi.org/10.1016/j.freeradbiomed.2010.09.013] [PMID:  20869432] 
[147] 
Entrez Gene: HSPA9 heat shock protein family A (Hsp70) member 9
[Homo sapiens (human)]. https://www.ncbi.nlm.nih.gov/gene/3313 (accessed 8 April 2019)
[148] 
Domanico, S.Z.; DeNagel, D.C.; Dahlseid, J.N.; Green, J.M.; Pierce, S.K. Cloning of the gene encoding peptide-binding protein 74 shows that it is a new member of the heat shock protein 70 family. Mol. Cell. Biol.,  1993, 13(6), 3598-3610.
[http://dx.doi.org/10.1128/MCB.13.6.3598] [PMID:  7684501] 
[149] 
Deocaris, C.C.; Kaul, S.C.; Wadhwa, R. On the brotherhood of the mitochondrial chaperones mortalin and heat shock protein 60. Cell Stress Chaperones,  2006, 11(2), 116-128.
[http://dx.doi.org/10.1379/CSC-144R.1] [PMID:  16817317] 
[150] 
Londono, C.; Osorio, C.; Gama, V.; Alzate, O. Mortalin, apoptosis, and neurodegeneration. Biomolecules,  2012, 2(1), 143-164.
[http://dx.doi.org/10.3390/biom2010143] [PMID:  24970131] 
[151] 
Osorio, C.; Sullivan, P.M.; He, D.N.; Mace, B.E.; Ervin, J.F.; Strittmatter, W.J.; Alzate, O. Mortalin is regulated by APOE in hippocampus of AD patients and by human APOE in TR mice. Neurobiol. Aging,  2007, 28(12), 1853-1862.
[http://dx.doi.org/10.1016/j.neurobiolaging.2006.08.011] [PMID:  17050040] 
[152] 
Qu, M.; Zhou, Z.; Xu, S.; Chen, C.; Yu, Z.; Wang, D. Mortalin overexpression attenuates beta-amyloid-induced neurotoxicity in SH-SY5Y cells. Brain Res.,  2011, 1368, 336-345.
[http://dx.doi.org/10.1016/j.brainres.2010.10.068] [PMID:  20974113] 
[153] 
Qu, M.; Zhou, Z.; Chen, C.; Li, M.; Pei, L.; Yang, J.; Wang, Y.; Li, L.; Liu, C.; Zhang, G.; Yu, Z.; Wang, D. Inhibition of mitochondrial permeability transition pore opening is involved in the protective effects of mortalin overexpression against beta-amyloid-induced apoptosis in SH-SY5Y cells. Neurosci. Res.,  2012, 72(1), 94-102.
[http://dx.doi.org/10.1016/j.neures.2011.09.009] [PMID:  22001761] 
[154] 
Martínez de Arrieta, C.; Morte, B.; Coloma, A.; Bernal, J. The human RC3 gene homolog, NRGN contains a thyroid hormone-responsive element located in the first intron. Endocrinology,  1999, 140(1), 335-343.
[http://dx.doi.org/10.1210/endo.140.1.6461] [PMID:  9886843] 
[155] 
Díez-Guerra, F.J. Neurogranin, a link between calcium/calmodulin and protein kinase C signaling in synaptic plasticity. IUBMB Life,  2010, 62(8), 597-606.
[http://dx.doi.org/10.1002/iub.357] [PMID:  20665622] 
[156] 
Kvartsberg, H.; Duits, F.H.; Ingelsson, M.; Andreasen, N.; Öhrfelt, A.; Andersson, K.; Brinkmalm, G.; Lannfelt, L.; Minthon, L.; Hansson, O.; Andreasson, U.; Teunissen, C.E.; Scheltens, P.; Van der Flier, W.M.; Zetterberg, H.; Portelius, E.; Blennow, K. Cerebrospinal fluid levels of the synaptic protein neurogranin correlates with cognitive decline in prodromal Alzheimer’s disease. Alzheimers Dement.,  2015, 11(10), 1180-1190.
[http://dx.doi.org/10.1016/j.jalz.2014.10.009] [PMID:  25533203] 
[157] 
De Vos, A.; Jacobs, D.; Struyfs, H.; Fransen, E.; Andersson, K.; Portelius, E.; Andreasson, U.; De Surgeloose, D.; Hernalsteen, D.; Sleegers, K.; Robberecht, C.; Van Broeckhoven, C.; Zetterberg, H.; Blennow, K.; Engelborghs, S.; Vanmechelen, E. C-terminal neurogranin is increased in cerebrospinal fluid but unchanged in plasma in Alzheimer’s disease. Alzheimers Dement.,  2015, 11(12), 1461-1469.
[http://dx.doi.org/10.1016/j.jalz.2015.05.012] [PMID:  26092348] 
[158] 
Thorsell, A.; Bjerke, M.; Gobom, J.; Brunhage, E.; Vanmechelen, E.; Andreasen, N.; Hansson, O.; Minthon, L.; Zetterberg, H.; Blennow, K. Neurogranin in cerebrospinal fluid as a marker of synaptic degeneration in Alzheimer’s disease. Brain Res.,  2010, 1362, 13-22.
[http://dx.doi.org/10.1016/j.brainres.2010.09.073] [PMID:  20875798] 
[159] 
Li, L.; Li, Y.; Ji, X.; Zhang, B.; Wei, H.; Luo, Y. The effects of retinoic acid on the expression of neurogranin after experimental cerebral ischemia. Brain Res.,  2008, 1226, 234-240.
[http://dx.doi.org/10.1016/j.brainres.2008.06.037] [PMID:  18602376] 
[160] 
Huang, K.P.; Huang, F.L.; Jäger, T.; Li, J.; Reymann, K.G.; Balschun, D. Neurogranin/RC3 enhances long-term potentiation and learning by promoting calcium-mediated signaling. J. Neurosci.,  2004, 24(47), 10660-10669.
[http://dx.doi.org/10.1523/JNEUROSCI.2213-04.2004] [PMID:  15564582] 
[161] 
Ueda, K.; Clark, D.P.; Chen, C.J.; Roninson, I.B.; Gottesman, M.M.; Pastan, I. The human multidrug resistance (mdr1) gene. cDNA cloning and transcription initiation. J. Biol. Chem.,  1987, 262(2), 505-508.
[PMID: 3027054] 
[162] 
Bell, D.R.; Trent, J.M.; Willard, H.F.; Riordan, J.R.; Ling, V. Chromosomal location of human P-glycoprotein gene sequences. Cancer Genet. Cytogenet.,  1987, 25(1), 141-148.
[http://dx.doi.org/10.1016/0165-4608(87)90169-5] [PMID:  2879621] 
[163] 
van Assema, D.M.; Lubberink, M.; Bauer, M.; van der Flier, W.M.; Schuit, R.C.; Windhorst, A.D.; Comans, E.F.; Hoetjes, N.J.; Tolboom, N.; Langer, O.; Müller, M.; Scheltens, P.; Lammertsma, A.A.; van Berckel, B.N. Blood-brain barrier P-glycoprotein function in Alzheimer’s disease. Brain,  2012, 135(Pt 1), 181-189.
[http://dx.doi.org/10.1093/brain/awr298] [PMID:  22120145] 
[164] 
Jeynes, B.; Provias, J. P-Glycoprotein altered expression in alzheimer’s disease: regional anatomic variability. J. Neurodegener. Dis.,  2013, 2013257953
[http://dx.doi.org/10.1155/2013/257953] [PMID:  26316985] 
[165] 
Zhang, C.; Qin, H.; Zheng, R.; Wang, Y.; Yan, T.; Huan, F.; Han, Y.; Zhu, W.; Zhang, L. A new approach for Alzheimer’s disease treatment through P-gp regulation via ibuprofen. Pathol. Res. Pract.,  2018, 214(11), 1765-1771.
[http://dx.doi.org/10.1016/j.prp.2018.08.011] [PMID:  30139557] 
[166] 
Mohamed, L.A.; Keller, J.N.; Kaddoumi, A. Role of P-glycoprotein in mediating rivastigmine effect on amyloid-β brain load and related pathology in Alzheimer’s disease mouse model. Biochim. Biophys. Acta,  2016, 1862(4), 778-787.
[http://dx.doi.org/10.1016/j.bbadis.2016.01.013] [PMID:  26780497] 
[167] 
Chiu, C.; Miller, M.C.; Monahan, R.; Osgood, D.P.; Stopa, E.G.; Silverberg, G.D. P-glycoprotein expression and amyloid accumulation in human aging and Alzheimer’s disease: preliminary observations. Neurobiol. Aging,  2015, 36(9), 2475-2482.
[http://dx.doi.org/10.1016/j.neurobiolaging.2015.05.020] [PMID:  26159621] 
[168] 
Kimura, Y.; Tanaka, K. Regulatory mechanisms involved in the control of ubiquitin homeostasis. J. Biochem.,  2010, 147(6), 793-798.
[http://dx.doi.org/10.1093/jb/mvq044] [PMID:  20418328] 
[169] 
Wang, G.P.; Khatoon, S.; Iqbal, K.; Grundke-Iqbal, I. Brain ubiquitin is markedly elevated in Alzheimer disease. Brain Res.,  1991, 566(1-2), 146-151.
[http://dx.doi.org/10.1016/0006-8993(91)91692-T] [PMID:  1814531] 
[170] 
Verheijen, B.M.; Stevens, J.A.A.; Gentier, R.J.G.; van ’t Hekke, C.D.; van den Hove, D.L.A.; Hermes, D.J.H.P.; Steinbusch, H.W.M.; Ruijter, J.M.; Grimm, M.O.W.; Haupenthal, V.J.; Annaert, W.; Hartmann, T.; van Leeuwen, F.W. Paradoxical effects of mutant ubiquitin on Aβ plaque formation in an Alzheimer mouse model. Neurobiol. Aging,  2018, 72, 62-71.
[http://dx.doi.org/10.1016/j.neurobiolaging.2018.08.011] [PMID:  30216939] 
[171] 
Cole, G.M.; Timiras, P.S. Ubiquitin-protein conjugates in Alzheimer’s lesions. Neurosci. Lett.,  1987, 79(1-2), 207-212.
[http://dx.doi.org/10.1016/0304-3940(87)90698-7] [PMID:  2823191] 
[172] 
Rivera, E.J.; Goldin, A.; Fulmer, N.; Tavares, R.; Wands, J.R.; de la Monte, S.M. Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer’s disease: link to brain reductions in acetylcholine. J. Alzheimers Dis.,  2005, 8(3), 247-268.
[http://dx.doi.org/10.3233/JAD-2005-8304] [PMID:  16340083] 
[173] 
Steen, E.; Terry, B.M.; Rivera, E.J.; Cannon, J.L.; Neely, T.R.; Tavares, R.; Xu, X.J.; Wands, J.R.; de la Monte, S.M. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease--is this type 3 diabetes? J. Alzheimers Dis.,  2005, 7(1), 63-80.
[http://dx.doi.org/10.3233/JAD-2005-7107] [PMID:  15750215] 
[174] 
Talbot, K.; Wang, H.Y.; Kazi, H.; Han, L.Y.; Bakshi, K.P.; Stucky, A.; Fuino, R.L.; Kawaguchi, K.R.; Samoyedny, A.J.; Wilson, R.S.; Arvanitakis, Z.; Schneider, J.A.; Wolf, B.A.; Bennett, D.A.; Trojanowski, J.Q.; Arnold, S.E. Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J. Clin. Invest.,  2012, 122(4), 1316-1338.
[http://dx.doi.org/10.1172/JCI59903] [PMID:  22476197] 
[175] 
De Felice, F.G.; Vieira, M.N.; Bomfim, T.R.; Decker, H.; Velasco, P.T.; Lambert, M.P.; Viola, K.L.; Zhao, W.Q.; Ferreira, S.T.; Klein, W.L. Protection of synapses against Alzheimer’s-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc. Natl. Acad. Sci. USA,  2009, 106(6), 1971-1976.
[http://dx.doi.org/10.1073/pnas.0809158106] [PMID:  19188609] 
[176] 
Triani, F.; Tramutola, A.; Di Domenico, F.; Sharma, N.; Butterfield, D.A.; Head, E.; Perluigi, M.; Barone, E. Biliverdin reductase-A impairment links brain insulin resistance with increased Aβ production in an animal model of aging: Implications for Alzheimer disease. Biochim. Biophys. Acta Mol. Basis Dis.,  2018, 1864(10), 3181-3194.
[http://dx.doi.org/10.1016/j.bbadis.2018.07.005] [PMID:  29981845] 
[177] 
Caccamo, A.; Belfiore, R.; Oddo, S. Genetically reducing mTOR signaling rescues central insulin dysregulation in a mouse model of Alzheimer’s disease. Neurobiol. Aging,  2018, 68, 59-67.
[http://dx.doi.org/10.1016/j.neurobiolaging.2018.03.032] [PMID:  29729422] 
[178] 
Yamamoto, N.; Ishikuro, R.; Tanida, M.; Suzuki, K.; Ikeda-Matsuo, Y.; Sobue, K. Insulin-signaling Pathway Regulates the Degradation of Amyloid β-protein via Astrocytes. Neuroscience,  2018, 385, 227-236.
[http://dx.doi.org/10.1016/j.neuroscience.2018.06.018] [PMID:  29932983] 
[179] 
de la Monte, S.M. Brain insulin resistance and deficiency as therapeutic targets in Alzheimer’s disease. Curr. Alzheimer Res.,  2012, 9(1), 35-66.
[http://dx.doi.org/10.2174/156720512799015037] [PMID:  22329651] 
[180] 
Schubert, M.; Brazil, D.P.; Burks, D.J.; Kushner, J.A.; Ye, J.; Flint, C.L.; Farhang-Fallah, J.; Dikkes, P.; Warot, X.M.; Rio, C.; Corfas, G.; White, M.F. Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation. J. Neurosci.,  2003, 23(18), 7084-7092.
[http://dx.doi.org/10.1523/JNEUROSCI.23-18-07084.2003] [PMID:  12904469] 
[181] 
Schubert, M.; Gautam, D.; Surjo, D.; Ueki, K.; Baudler, S.; Schubert, D.; Kondo, T.; Alber, J.; Galldiks, N.; Küstermann, E.; Arndt, S.; Jacobs, A.H.; Krone, W.; Kahn, C.R.; Brüning, J.C. Role for neuronal insulin resistance in neurodegenerative diseases. Proc. Natl. Acad. Sci. USA,  2004, 101(9), 3100-3105.
[http://dx.doi.org/10.1073/pnas.0308724101] [PMID:  14981233] 
[182] 
Xu, H.; Chen, X.; Wang, J.; Yang, T.; Liu, N.; Cheng, J.; Gao, R.; Liu, J.; Xiao, H. Involvement of insulin signalling pathway in methamphetamine-induced hyperphosphorylation of Tau. Toxicology,  2018, 408, 88-94.
[http://dx.doi.org/10.1016/j.tox.2018.07.002] [PMID:  29981415] 
[183] 
Doi, T.; Shimada, H.; Makizako, H.; Tsutsumimoto, K.; Hotta, R.; Nakakubo, S.; Suzuki, T. Association of insulin-like growth factor-1 with mild cognitive impairment and slow gait speed. Neurobiol. Aging,  2015, 36(2), 942-947.
[http://dx.doi.org/10.1016/j.neurobiolaging.2014.10.035] [PMID:  25467636] 
[184] 
Gasperi, M.; Castellano, A.E. Growth hormone/insulin-like growth factor I axis in neurodegenerative diseases. J. Endocrinol. Invest.,  2010, 33(8), 587-591.
[http://dx.doi.org/10.1007/BF03346653] [PMID:  20930497] 
[185] 
Logan, S.; Pharaoh, G.A.; Marlin, M.C.; Masser, D.R.; Matsuzaki, S.; Wronowski, B.; Yeganeh, A.; Parks, E.E.; Premkumar, P.; Farley, J.A.; Owen, D.B.; Humphries, K.M.; Kinter, M.; Freeman, W.M.; Szweda, L.I.; Van Remmen, H.; Sonntag, W.E. Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-β uptake in astrocytes. Mol. Metab.,  2018, 9, 141-155.
[http://dx.doi.org/10.1016/j.molmet.2018.01.013] [PMID:  29398615] 
[186] 
Blaustein, M.P. Calcium transport and buffering in neurons. Trends Neurosci.,  1988, 11(10), 438-443.
[http://dx.doi.org/10.1016/0166-2236(88)90195-6] [PMID:  2469161] 
[187] 
Heizmann, C.W.; Braun, K. Changes in Ca(2+)-binding proteins in human neurodegenerative disorders. Trends Neurosci.,  1992, 15(7), 259-264.
[http://dx.doi.org/10.1016/0166-2236(92)90067-I] [PMID:  1381122] 
[188] 
Kojetin, D.J.; Venters, R.A.; Kordys, D.R.; Thompson, R.J.; Kumar, R.; Cavanagh, J. Structure, binding interface and hydrophobic transitions of Ca2+-loaded calbindin-D(28K). Nat. Struct. Mol. Biol.,  2006, 13(7), 641-647.
[http://dx.doi.org/10.1038/nsmb1112] [PMID:  16799559] 
[189] 
Rogers, J.H. Calretinin: a gene for a novel calcium-binding protein expressed principally in neurons. J. Cell Biol.,  1987, 105(3), 1343-1353.
[http://dx.doi.org/10.1083/jcb.105.3.1343] [PMID:  3654755] 
[190] 
Altobelli, G.G.; Cimini, D.; Esposito, G.; Iuvone, T.; Cimini, V. Analysis of calretinin early expression in the rat hippocampus after beta amyloid (1-42) peptide injection. Brain Res.,  2015, 1610, 89-97.
[http://dx.doi.org/10.1016/j.brainres.2015.03.029] [PMID:  25813826] 
[191] 
Mattson, M.P.; Rychlik, B.; Chu, C.; Christakos, S. Evidence for calcium-reducing and excito-protective roles for the calcium-binding protein calbindin-D28k in cultured hippocampal neurons. Neuron,  1991, 6(1), 41-51.
[http://dx.doi.org/10.1016/0896-6273(91)90120-O] [PMID:  1670921] 
[192] 
Iacopino, A.M.; Christakos, S. Specific reduction of calcium-binding protein (28-kilodalton calbindin-D) gene expression in aging and neurodegenerative diseases. Proc. Natl. Acad. Sci. USA,  1990, 87(11), 4078-4082.
[http://dx.doi.org/10.1073/pnas.87.11.4078] [PMID:  2140897] 
[193] 
Mikkonen, M.; Alafuzoff, I.; Tapiola, T.; Soininen, H.; Miettinen, R. Subfield- and layer-specific changes in parvalbumin, calretinin and calbindin-D28K immunoreactivity in the entorhinal cortex in Alzheimer’s disease. Neuroscience,  1999, 92(2), 515-532.
[http://dx.doi.org/10.1016/S0306-4522(99)00047-0] [PMID:  10408601] 
[194] 
Hof, P.R.; Nimchinsky, E.A.; Celio, M.R.; Bouras, C.; Morrison, J.H. Calretinin-immunoreactive neocortical interneurons are unaffected in Alzheimer’s disease. Neurosci. Lett.,  1993, 152(1-2), 145-148.
[http://dx.doi.org/10.1016/0304-3940(93)90504-E] [PMID:  8515868] 
[195] 
Zallo, F.; Gardenal, E.; Verkhratsky, A.; Rodríguez, J.J. Loss of calretinin and parvalbumin positive interneurones in the hippocampal CA1 of aged Alzheimer’s disease mice. Neurosci. Lett.,  2018, 681, 19-25.
[http://dx.doi.org/10.1016/j.neulet.2018.05.027] [PMID:  29782955] 
[196] 
Donlon, T.A.; Krensky, A.M.; Wallace, M.R.; Collins, F.S.; Lovett, M.; Clayberger, C. Localization of a human T-cell-specific gene, RANTES (D17S136E), to chromosome 17q11.2-q12. Genomics,  1990, 6(3), 548-553.
[http://dx.doi.org/10.1016/0888-7543(90)90485-D] [PMID:  1691736] 
[197] 
Rostene, W.; Buckingham, J.C. Chemokines as modulators of neuroendocrine functions. J. Mol. Endocrinol.,  2007, 38(3), 351-353.
[http://dx.doi.org/10.1677/JME-07-0006] [PMID:  17339397] 
[198] 
Valerio, A.; Ferrario, M.; Martinez, F.O.; Locati, M.; Ghisi, V.; Bresciani, L.G.; Mantovani, A.; Spano, P. Gene expression profile activated by the chemokine CCL5/RANTES in human neuronal cells. J. Neurosci. Res.,  2004, 78(3), 371-382.
[http://dx.doi.org/10.1002/jnr.20250] [PMID:  15389840] 
[199] 
Sanchez, A.; Tripathy, D.; Grammas, P. RANTES release contributes to the protective action of PACAP38 against sodium nitroprusside in cortical neurons. Neuropeptides,  2009, 43(4), 315-320.
[http://dx.doi.org/10.1016/j.npep.2009.05.002] [PMID:  19497618] 
[200] 
Lin, M.S.; Hung, K.S.; Chiu, W.T.; Sun, Y.Y.; Tsai, S.H.; Lin, J.W.; Lee, Y.H. Curcumin enhances neuronal survival in N-methyl-d-aspartic acid toxicity by inducing RANTES expression in astrocytes via PI-3K and MAPK signaling pathways. Prog. Neuropsychopharmacol. Biol. Psychiatry,  2011, 35(4), 931-938.
[http://dx.doi.org/10.1016/j.pnpbp.2010.12.022] [PMID:  21199667] 
[201] 
Haskins, M.; Jones, T.E.; Lu, Q.; Bareiss, S.K. Early alterations in blood and brain RANTES and MCP-1 expression and the effect of exercise frequency in the 3xTg-AD mouse model of Alzheimer’s disease. Neurosci. Lett.,  2016, 610, 165-170.
[http://dx.doi.org/10.1016/j.neulet.2015.11.002] [PMID:  26547034] 
[202] 
Tripathy, D.; Thirumangalakudi, L.; Grammas, P. RANTES upregulation in the Alzheimer’s disease brain: a possible neuroprotective role. Neurobiol. Aging,  2010, 31(1), 8-16.
[http://dx.doi.org/10.1016/j.neurobiolaging.2008.03.009] [PMID:  18440671] 
[203] 
Kosik, K.S.; Orecchio, L.D.; Bruns, G.A.; Benowitz, L.I.; MacDonald, G.P.; Cox, D.R.; Neve, R.L. Human GAP-43: its deduced amino acid sequence and chromosomal localization in mouse and human. Neuron,  1988, 1(2), 127-132.
[http://dx.doi.org/10.1016/0896-6273(88)90196-1] [PMID:  3272162] 
[204] 
Benowitz, L.I.; Routtenberg, A. GAP-43: an intrinsic determinant of neuronal development and plasticity. Trends Neurosci.,  1997, 20(2), 84-91.
[http://dx.doi.org/10.1016/S0166-2236(96)10072-2] [PMID:  9023877] 
[205] 
Holahan, M.R.; Honegger, K.S.; Tabatadze, N.; Routtenberg, A. GAP-43 gene expression regulates information storage. Learn. Mem.,  2007, 14(6), 407-415.
[http://dx.doi.org/10.1101/lm.581907] [PMID:  17554085] 
[206] 
Sandelius, Å.; Portelius, E.; Källén, Å.; Zetterberg, H.; Rot, U.; Olsson, B.; Toledo, J.B.; Shaw, L.M.; Lee, V.M.Y.; Irwin, D.J.; Grossman, M.; Weintraub, D.; Chen-Plotkin, A.; Wolk, D.A.; McCluskey, L.; Elman, L.; Kostanjevecki, V.; Vandijck, M.; McBride, J.; Trojanowski, J.Q.; Blennow, K. Elevated CSF GAP-43 is Alzheimer’s disease specific and associated with tau and amyloid pathology. Alzheimers Dement.,  2019, 15(1), 55-64.
[http://dx.doi.org/10.1016/j.jalz.2018.08.006] [PMID:  30321501] 
[207] 
Ono, Y.; Sorimachi, H. Calpains: an elaborate proteolytic system. Biochim. Biophys. Acta,  2012, 1824(1), 224-236.
[http://dx.doi.org/10.1016/j.bbapap.2011.08.005] [PMID:  21864727] 
[208] 
Baudry, M.; Bi, X. Calpain-1 and Calpain-2: The Yin and Yang of Synaptic Plasticity and Neurodegeneration. Trends Neurosci.,  2016, 39(4), 235-245.
[http://dx.doi.org/10.1016/j.tins.2016.01.007] [PMID:  26874794] 
[209] 
Vaisid, T.; Kosower, N.S.; Katzav, A.; Chapman, J.; Barnoy, S. Calpastatin levels affect calpain activation and calpain proteolytic activity in APP transgenic mouse model of Alzheimer’s disease. Neurochem. Int.,  2007, 51(6-7), 391-397.
[http://dx.doi.org/10.1016/j.neuint.2007.04.004] [PMID:  17513017] 
[210] 
Touyarot, K.; Poussard, S.; Cortes-Torrea, C.; Cottin, P.; Micheau, J. Effect of chronic inhibition of calpains in the hippocampus on spatial discrimination learning and protein kinase C. Behav. Brain Res.,  2002, 136(2), 439-448.
[http://dx.doi.org/10.1016/S0166-4328(02)00188-2] [PMID:  12429406] 
[211] 
Mehta, D.; Jackson, R.; Paul, G.; Shi, J.; Sabbagh, M. Why do trials for Alzheimer’s disease drugs keep failing? A discontinued drug perspective for 2010-2015. Expert Opin. Investig. Drugs,  2017, 26(6), 735-739.
[http://dx.doi.org/10.1080/13543784.2017.1323868] [PMID:  28460541] 
Cite As
Current Neuropharmacology

A Comprehensive Review of Alzheimer’s Association with Related Proteins: Pathological Role and Therapeutic Significance

Abstract

Graphical Abstract
