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Current Alzheimer Research

Author(s): Lisa Schrott, Ping Yi, Kasey Jackson, Gabriel S. Jackson, Christopher Webb, Alireza Minagar, J. Winny Yun, Geoffrey Purdum, David J. Rios, Theodore A. Tyler, Maria I. Vizcanio, Judith L. Castor, Trevor Castor and Jonathan S. Alexander*

DOI: 10.2174/1567205018666210218155835

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Nanoparticle-Encapsulated Bryostatin-1 Activates α-Secretase and PKC Isoforms In vitro and Facilitates Acquisition and Retention of Spatial Learning in an Alzheimer's Disease Mouse Model

Page: [1302 - 1310] Pages: 9

  • * (Excluding Mailing and Handling)

Abstract

Background: Alzheimer’s disease (AD) animal models have revealed neuroprotective actions of Bryostatin-1 mediated by activation of novel PKC isoforms, suppression of beta-amyloid and downregulation of inflammatory and angiogenic events, making Bryostatin-1 an attractive candidate for attenuating AD-associated neural, vascular, and cognitive disturbances.

Objective: To further enhance Bryostatin-1 efficacy, nanoparticle-encapsulated Bryostatin-1 formulations were prepared.

Methods: We compared nano-encapsulated and unmodified Bryostatin-1 in in vitro models of neuronal PKC-d, PKC-e isoforms, α-secretase and studied nano-encapsulated Bryostatin-1 in an AD mouse model of spatial memory (BC3-Tg (APPswe, PSEN1 dE9) 85Dbo/J mice).

Results: We found that nanoencapsulated Bryostatin-1 formulations displayed activity greater or equal to that of unmodified Bryostatin-1 in PKC-δ and -ε and α-secretase activation assays. We next evaluated how treatment with a nanoencapsulated Bryostatin-1 formulation facilitated spatial learning in the Morris water maze. AD transgenic mice (6.5 to 8 months of age) were treated with nanoparticle encapsulated Bryostatin-1 formulation (1, 2.5, or 5 μg/mouse) three times the week before testing and then daily for each of the 5 days of testing. Across the acquisition phase, mice treated with nanoencapsulated Bryostatin-1 had shorter latencies, increased % time in the target zone and decreased % time in the opposite quadrant. The mice were given retention testing after a 2-week period without drug treatment. Mice treated with nanoencapsulated Bryostatin-1 had shorter latencies to find the escape platform, indicating retention of spatial memory.

Conclusion: These data suggest that cognitive deficits associated with AD could be treated using highly potent nanoparticle-encapsulated formulations of Bryostatin-1.

Keywords: Alzheimer's, dementia, secretase, PKC, neurodegenerative disease, cerebral cortex.

[1]
Borchelt DR, Ratovitski T, van Lare J, et al. Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 1997; 19(4): 939-45.
[http://dx.doi.org/10.1016/S0896-6273(00)80974-5] [PMID: 9354339]
[2]
van Groen T, Kiliaan AJ, Kadish I. Deposition of mouse amyloid beta in human APP/PS1 double and single AD model transgenic mice. Neurobiol Dis 2006; 23(3): 653-62.
[http://dx.doi.org/10.1016/j.nbd.2006.05.010] [PMID: 16829076]
[3]
Saura CA, Chen G, Malkani S, et al. Conditional inactivation of presenilin 1 prevents amyloid accumulation and temporarily rescues contextual and spatial working memory impairments in amyloid precursor protein transgenic mice. J Neurosci 2005; 25(29): 6755-64.
[http://dx.doi.org/10.1523/JNEUROSCI.1247-05.2005] [PMID: 16033885]
[4]
Demattos RB, Lu J, Tang Y, et al. A plaque-specific antibody clears existing β-amyloid plaques in Alzheimer’s disease mice. Neuron 2012; 76(5): 908-20.
[http://dx.doi.org/10.1016/j.neuron.2012.10.029] [PMID: 23217740]
[5]
Salloway S, Sperling R, Fox NC, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 2014; 370(4): 322-33.
[http://dx.doi.org/10.1056/NEJMoa1304839] [PMID: 24450891]
[6]
Yi P, Schrott L, Castor TP, Alexander JS. Bryostatin-1 vs. TPPB: Dose-dependent APP processing and PKC-α, -δ, and -ε isoform activation in SH-SY5Y neuronal cells. J Mol Neurosci 2012; 48(1): 234-44.
[http://dx.doi.org/10.1007/s12031-012-9816-3] [PMID: 22700373]
[7]
Schrott LM, Jackson K, Yi P, et al. Acute oral Bryostatin-1 administration improves learning deficits in the APP/PS1 transgenic mouse model of Alzheimer’s disease. Curr Alzheimer Res 2015; 12(1): 22-31.
[http://dx.doi.org/10.2174/1567205012666141218141904] [PMID: 25523423]
[8]
Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT. Inflammation as a central mechanism in Alzheimer’s disease. Alzheimers Dement (N Y) 2018; 4: 575-90.
[http://dx.doi.org/10.1016/j.trci.2018.06.014] [PMID: 30406177]
[9]
Carpenter AC, Alexander JS. Endothelial PKC delta activation attenuates neutrophil transendothelial migration. Inflamm Res 2008; 57(5): 216-29.
[http://dx.doi.org/10.1007/s00011-007-7031-4] [PMID: 18594782]
[10]
Nezhat F, Wadler S, Muggia F, et al. Phase II trial of the combination of bryostatin-1 and cisplatin in advanced or recurrent carcinoma of the cervix: A New York Gynecologic Oncology Group study. Gynecol Oncol 2004; 93(1): 144-8.
[http://dx.doi.org/10.1016/j.ygyno.2003.12.021] [PMID: 15047228]
[11]
Wang D, Darwish DS, Schreurs BG, Alkon DL. Analysis of long-term cognitive-enhancing effects of bryostatin-1 on the rabbit (Oryctolagus cuniculus) nictitating membrane response. Behav Pharmacol 2008; 19(3): 245-56.
[http://dx.doi.org/10.1097/FBP.0b013e3282feb0d2] [PMID: 18469542]
[12]
Hongpaisan J, Sun M-K, Alkon DL. PKC ε activation prevents synaptic loss, Aβ elevation, and cognitive deficits in Alzheimer’s disease transgenic mice. J Neurosci 2011; 31(2): 630-43.
[http://dx.doi.org/10.1523/JNEUROSCI.5209-10.2011] [PMID: 21228172]
[13]
Lagadec S, Rotureau L, Hémar A, et al. Early temporal short-term memory deficits in double transgenic APP/PS1 mice. Neurobiol Aging 2012; 33(1): 203.e1-203.e11.
[http://dx.doi.org/10.1016/j.neurobiolaging.2010.07.023] [PMID: 20817351]
[14]
Lalonde R, Fukuchi K, Strazielle C. Neurologic and motor dysfunctions in APP transgenic mice. Rev Neurosci 2012; 23(4): 363-79.
[http://dx.doi.org/10.1515/revneuro-2012-0041] [PMID: 23089603]
[15]
Davis CP, Franklin LM, Johnson GS, Schrott LM. Prenatal oxycodone exposure impairs spatial learning and/or memory in rats. Behav Brain Res 2010; 212(1): 27-34.
[http://dx.doi.org/10.1016/j.bbr.2010.03.022] [PMID: 20307587]
[16]
Janus C. Search strategies used by APP transgenic mice during navigation in the Morris water maze. Learn Mem 2004; 11(3): 337-46.
[http://dx.doi.org/10.1101/lm.70104] [PMID: 15169864]
[17]
Guo C, Wang T, Zheng W, Shan Z-Y, Teng W-P, Wang Z-Y. Intranasal deferoxamine reverses iron-induced memory deficits and inhibits amyloidogenic APP processing in a transgenic mouse model of Alzheimer’s disease. Neurobiol Aging 2013; 34(2): 562-75.
[http://dx.doi.org/10.1016/j.neurobiolaging.2012.05.009] [PMID: 22717236]
[18]
Szallasi Z, Smith CB, Pettit GR, Blumberg PM. Differential regulation of protein kinase C isozymes by bryostatin 1 and phorbol 12-myristate 13-acetate in NIH 3T3 fibroblasts. J Biol Chem 1994; 269(3): 2118-4.