Alzheimer’s disease (AD) is currently the most prominent form of dementia among the elderly. Although AD manifests in late adult life, it is not clear when the disease actually starts and how long the neuropathological processes take to develop AD. The major unresolved question is the timing and the nature of triggering leading to AD. Is it an early or developmental and/or late phenomenon and what are the factors that trigger the cascade of pathobiochemical processes? To explain the etiology of AD one should consider the neuropathological features, such as neuronal cell death, τ tangles, and amyloid plaque, and environmental factors associated with AD, such as diet, toxicological exposure, and hormonal factors. Current dominant theories of AD etiology are “protein–only”, they attribute the cause of the disease directly to the activities of associated proteins once they have been produced; the major limitation is that protein aggregations occur “late in the game”. Development and progression of AD has not been explained by protein–only models. In view of this limitation, we propose a “Latent Early-Life Associated Regulation” (LEARn) model, which postulates a latent expression of specific genes triggered at the developmental stage. According to this model, environmental agents (e.g., heavy metals), intrinsic factors (e.g., cytokines), and dietary factors (e.g., cholesterol) perturb gene regulation in a long–term fashion, beginning at early developmental stages; however, these perturbations do not have pathological results until significantly later in life. For example, such actions would perturb APP gene regulation at very early stage via its transcriptional machinery, leading to delayed overexpression of APP and subsequently of Aβ deposition. This model operates on the regulatory region (promoter) of the gene and by the effect of methylation at certain sites within the promoter of specific genes. Promoters tend to have both positive and negative regulatory elements, and promoter activity can be altered by changes in the primary DNA sequence and by epigenetic changes through mechanisms such as DNA methylation at CpG dinucleotides or oxidation of guanosine residues. The basis of the LEARn model is that environmental factors, including metals and dietary factors, operate by interfering the interaction of methylated CpG clusters with binding proteins, such as MeCP2 and SP1. The LEARn model may explain the etiology of AD and other neuropsychiatric and developmental disorders.

The amyloid cascade hypothesis is a well known hypothesis describing the pathogenesis of Alzheimer’s disease (AD). Based on this hypothesis, many dugs, which contribute to the inhibition of amyloid β-protein (Aβ) generation and aggregation, or to the enhancement of extracellular Aβ removal, are currently under clinical trials. Intracellular Aβ may be even more important than extracellular Aβ, since intraneuronal Aβ accumulation commonly precedes extracellular Aβ deposition in several familial AD-related mutant presenilin 1-transgenic mice. Various pathogenic mechanisms involving intracellular Aβ such as mitochondrial toxicity, proteasome impairment and synaptic damage have been suggested. In addition, we have reported that intracellular Aβ42 accumulation may enhance p53-related apoptosis. Thus, we searched for a novel drug that promotes degradation of intracellular Aβ, and have recently found apomorphine (APO). In addition, APO treatment improved memory function and AD pathology in an AD mouse model, 3xTg-AD, proving to become a promising cure for AD. In this article, the pathogenicity of intracellular Aβ and potential of APO for the therapeutics in AD are reviewed.

It is widely accepted that Aβ42 aggregation is a central event in the pathogenesis of Alzheimer's disease. Aβ42 oligomers and fibrils cause the breakdown of neural circuits, neuronal death and eventually dementia. There are a number of physiological molecules that can protect Aβ42 from aggregation. Promoting such protective molecules and mechanisms against Aβ42 aggregation may be a novel direction in AD drug discovery. One of the most striking protective molecules is none other than Aβ40, which inhibits Aβ42 aggregation in a specific and dosage dependent manner. Aβ40 is a critical, built-in mechanism against Aβ42 aggregation. A number of other molecules and mechanisms also inhibit Aβ42 aggregation, such as heat shock proteins, L-PGDS, heme and methionine oxidation. The relevance of these protective mechanisms to AD pathogenesis and intervention is discussed.

The medial temporal lobe-dependent memory loss associated with Alzheimer’s disease (AD) is often accompanied by a loss of prefrontal cortex-dependent cognitive domains that fall under the broad category of executive function. In this study, we examined the relationship between one type of prefrontal-dependent executive function, discrimination reversal learning, and levels of the amyloid beta protein (Aβ) of 40 and 42 residues in a transgenic mouse model (Tg2576) of the over-expression of the familial AD mutant form of the amyloid precursor protein (APPsw). Tg2576 and their non-transgenic (NTg) littermates were assessed at 3 and 6 months of age when there is little to no amyloid plaque deposition. After reversal learning assessment, Aβ40 and Aβ42 were quantified in the prefrontal cortex and hippocampus. Tg2576 mice were impaired in reversal learning at 6 but not 3 months of age when compared to the NTg group. Coincidently, there was a corresponding approximately 3-fold increase of Aβ42 levels in the prefrontal cortex of 6- compared to 3-month-old Tg2576 mice. In addition, the prefrontal cortex contained higher levels of Aβ42 compared to the hippocampus at both 3 and 6 months of age, regardless of genotype, indicating a high vulnerability of this brain region to Aβ42 accumulation. These data suggest that the early emergence of reversal learning deficits in the Tg2576 mouse may be due to the localized increase of Aβ42 in the prefrontal cortex.

Alzheimer's disease (AD) is by far the most common form of dementia in the elderly and concerns one out of three individuals over 85. Like other neurodegenerative disorders such as Parkinson, Hungtington or prion diseases, AD is characterized by the formation of amyloid plaques in the central nervous system. In the brain of AD patients, the main component of these abnormal deposits is an aggregated form of the so-called amyloid β-peptide (Aβ), which is produced from a large trans-membrane type-1 protein, the β-amyloid precursor protein (βAPP), by the sequential action of the β- and γ-secretases. Beside these two amyloidogenic proteolytic attacks, βAPP is targeted by a third enzyme termed α-secretase. Of utmost importance, this cleavage, which can be of constitutive or regulated origin, occurs right in the middle of the Aβ sequence, thus precluding its production. For this reason, and because the sAPPα secreted fragment derived from this cleavage displays beneficial effects, tremendous efforts have been made recently in order to both identify the proteases involved and the way they are regulated. More recently, it emerged that α-secretase was also responsible for the physiological processing of the cellular prion protein (PrP^c) in the middle of its toxic 106-126 sequence. This review will focus on the recent advances in the α-secretase pathways regulation and will discuss the putative therapeutic approaches that could be envisioned concerning the treatment of two apparently distinct diseases that share common denominators according to their metabolism.

Accumulation of amyloid β-peptides (Aβ) in the brain is believed to contribute to the development of Alzheimer disease (AD). Aβ, a 40-42 amino acid-comprising proteolytical fragment of the amyloid precursor protein (APP), is released from APP by sequential cleavages via β- and γ-secretases. However, the predominant route of APP processing consists of successive cleavages by α- and γ-secretases. Alpha-secretase attacks APP inside the Aβ sequence, and therefore prevents formation of neurotoxic Aβ. After cleavage by α-secretase, the soluble N-terminal domain of APP, which possesses neurotrophic and neuroprotective properties, is released. In AD patients, a decrease in α-secretase processing of APP has been found and therefore, strategies to improve α-secretase activity are obvious. Several years after descriptive reports on α-secretase, the responsible enzyme(s) have been identified to belong to the family of A Disintegrin And Metalloproteinase (ADAM). Three of these membrane-anchored zinc-dependent metalloproteinases, ADAM10 as well as ADAM17 and perhaps also ADAM9 display α-secretase activity. Since the individual knock-out of these proteinases in neither case completely prevented α-secretase processing of APP, it seems likely that different ADAMs are mutually compensating, and under particular conditions conduct α-secretase cleavage of APP. In addition to ADAMs, perhaps other membrane-associated metalloproteinases contribute to the shedding of APP. Stimulation of α-secretase activity can be achieved via several signaling cascades including phospholipase C, phosphatidylinositol 3-kinase and serine/threonine-specific kinases such as protein kinases C, and mitogen-activated protein kinases. Calcium ions, direct activation of protein kinase C and stimulation of distinct G protein-coupled receptors, receptor tyrosine kinases and ligand-regulated ion channels are known to increase α-secretase processing of APP. Serotonin uptake inhibitors and ion channel agonists are in clinical trials to test their efficiency in the treatment of AD.

Major hallmarks of Alzheimer’s disease (AD) include brain deposition of the amyloid–β peptide (Aβ), which is proteolytically cleaved from a large Aβ precursor protein (APP) by β and γ– secretases. A transmembrane aspartyl protease, β–APP cleaving enzyme (BACE1), has been recognized as the β–secretase. We review the structure and function of the BACE1 protein, and of 4129 bp of the 5’–flanking region sequence of the BACE1 gene and its interaction with various transcription factors involved in cell signaling. The promoter region and 5’–untranslated region (UTR) contain multiple transcription factor binding sites, such as AP–1, CREB and MEF2. A 91 bp fragment is the shortest region with significant reporter gene activity and constitutes the minimal promoter element for BACE1. The BACE1 promoter contains six unique functional domains and three structural domains of increasing sequence complexity as the “ATG” start codon is approached. Notably, the BACE1 gene promoter contains basal regulatory elements, inducible features and sites for regulation by various important transcription factors. Herein, we also discuss and speculate how the interaction of these transcription factors with the BACE1 promoter can modulate synaptic plasticity, neuronal apoptosis and oxidative stress, which are pertinent to the pathogenesis and progression of AD.

Here we discuss the biology of γ-secretase, an enigmatic enzyme complex that is responsible for the generation of the β-amyloid peptide that constitutes the amyloid plaques of Alzheimer’s disease. We begin with a brief review on the processing of the amyloid precursor protein and a brief discussion on the family of enzymes involved in regulated intramembrane proteolysis, of which γ-secretase is a member. We then identify the four major components of the γ-secretase complex – presenilin, nicastrin, Aph-1, and Pen-2 – with a focus on the identification of each and the role that each plays in the maturation and activity of the complex. Next, we summarize the known subcellular locations of each γ-secretase component and the sites of γ-secretase activity, as defined by the production of β-amyloid. Finally, we close by synthesizing all of the included topics into an overarching model for the assembly and trafficking of the γ-secretase complex, which serves as a launching point for further questions into the biology and function of γ-secretase in Alzheimer’s disease.

Alzheimer’s disease (AD) is a neurological disorder characterized by plaques deposition, neurofibrillary tangle formation and an elevated inflammation. Specifically, increased expression of interleukin (IL)-1β and tumour necrosis factor (TNF)-α have been observed in AD cerebrospinal fluid and temporal brain tissue. Conversely, epidemiological studies have shown that use of non-steroidal anti-inflammatory drugs (NSAIDs) by the elderly is often associated with a decreased relative risk and a delayed onset of AD. IL-1β and TNF-α genes were shown to carry genetic polymorphisms that increase the risk of developing common AD. Studies have also established the apolipoprotein E (apoE) gene to be a risk factor for AD, with ε4 carriers having been found to show lower levels of brain apoE protein. In the present study, treatment with IL-1β induced a significant increase in extracellular apoE protein in primary rat mixed glial cells but not in astrocyte cultures. Similarly, treatment of primary rat mixed glial cell cultures with the common NSAIDs, indomethacin and aspirin, induced significant increases in extracellular apoE protein levels. In contrast, treatment of primary rat astrocyte and mixed glial cell cultures with TNF-α significantly reduced extracellular apoE protein levels. These results are consistent with the notion that apoE is an actor of inflammation modulation since its release is regulated by pro-inflammatory cytokines and dampened by NSAIDs. This further supports the idea that elevated cytokine expression in AD directly modulates inflammation and indirectly apoEmediated neuronal remodelling.

The LDL-receptor gene family constitutes a class of structurally closely related cell surface receptors fulfilling diverse functions in different organs, tissues, and cell types. The LDL-receptor is the prototype of this family, which also includes the VLDLR, ApoER2/LRP8, LRP1 and LRP1B, as well as Megalin/GP330, SorLA-1/LR11, LRP5, LRP6 and MEGF7. Recently several lines of evidence have positioned the LDL receptor gene family as one of the key players in Alzheimer’s disease (AD) research. Initially this receptor family was of high interest due to its key function in cholesterol/apolipoprotein E (ApoE) uptake, with the ε4 allele of ApoE as the strongest genetic risk factor for late-onset AD. It has been established that the cholesterol metabolism of the cell has a strong impact on the production of Aβ, the major component of the plaques found in the brain of AD-patients. The original report that soluble amyloid precursor protein (APP) containing the kunitz proteinase inhibitor (KPI) domain might act as a ligand for LRP1 led to a complex investigation of the interaction of both proteins and their potential function in AD development. Meanwhile, it has been demonstrated that LRP1 might bind to APP independent of the KPI domain in APP. This APP – LRP1 interaction is facilitated through a trimeric complex of APP-FE65-LRP1, which has a functional role in APP processing. Along with LRP1, APP is transported from the early secretory compartments to the cell surface and subsequently internalised into the endosomal / lysosomal compartments. Recent investigations indicate that VLDLR, ApoER2 and SorLA fulfil a similar role in shifting APP localisation in the cell, which affects APP processing and the production of the APP derived Amyloid β-peptide (Aβ).

In addition to the effect of lipoprotein receptors on APP processing and Aβ production, LRP1 has been shown to bind Aβ directly or indirectly through Aβ-lactoferrin, Aβ-α2M and Aβ-ApoE complexes in vitro and in vivo. Therefore based on these observations two LRP1 mediated clearance mechanisms of Aβ are proposed to play a crucial role in the prevention of AD: either Aβ-uptake into a cell with its subsequent degradation or its transport out of the brain over the blood brain barrier into the periphery. Following this export Aβ is degraded in the liver, where LRP1 potentially conducts the removal of Aβ from the blood stream.

Although the involvement of LDL-R-family members in AD is not yet fully understood it becomes clear that they can directly affect APP production, Aβ-clearance and Aβ-transport over the blood brain barrier as well as NMDA receptor function.

The accumulation of hyperphosphorylated tau is a common feature of several dementias. Tau is one of the brain microtubule–associated proteins. Here, we discuss tau’s function in microtubule assembly and stabilization with regards to tau’s interactions with other proteins, membranes, and DNA. We describe and analyze important posttranslational modifications: hyperphosphorylation, glycosylation, ubiquitination, glycation, polyamination, nitration, acetylation, methylation, and truncation. We discuss how these post-translational modifications can alter tau’s biological functions and what is known about tau self-assembly, and we propose a mechanism of tau polymerization. We analyze the impact of natural mutations on tau that cause fronto-temporal dementia associated with chromosome 17 (FTDP-1 7). Finally, we consider whether tau accumulation or its conformational change is related to tau-induced neurodegeneration, and we propose a mechanism of neurodegeneration.

Objetive: The study aimed to describe the prevalence and severity of neuropsychiatric symptoms in patients with Alzheimer’s disease (AD) and vascular dementia (VaD).

Patients and methods: We prospectively studied 65 patients with dementia, 37 met the criteria of NINCDS-ADRDA for probable AD and 28 the clinical and radiological criteria of NINDS-AIREN for VaD. Among VaD patients, 22 met the radiological criteria for subcortical VaD. The Minimental State Examination (MMSE) and the Neuropsychiatric Inventory (NPI) were used to evaluate cognitive and neuropsychiatric symptoms. All patients underwent a neuroimaging study (CT scan and/or MRI). Patients were not treated with antidementia or psychotropic drugs.

Results: Age, gender, educational level and MMSE scores did not differ between patients (p >0.05). The total prevalence of neuropsychiatric symptoms was similar in both groups (AD 94.6% vs. VaD 96.4%, p= 0.727). Sleep disturbances (35.1% vs. 3.6%, p =0.002) and appetite changes (37.8% vs. 14.3%, p = 0.032) were more prevalent in AD patients than in VaD patients who met the NINDS-AIREN criteria. Sleep disturbances (35.1% vs. 4.5%, p =0.008), appetite changes (37.8% vs. 13.6%, p = 0.047) and aberrant motor behaviour (24.3% vs. 0%, p =0.012) were more prevalent in AD patients than in subcortical VaD. The total scores for sleep disturbance, appetite changes and aberrant motor behaviour were higher in AD patients (p < 0.05).

Conclusions: There were no significant differences between AD and VaD patients, except that sleep disturbances, appetite changes and aberrant motor behaviour that were more prevalent and severe in AD.

In Alzheimer’s disease (AD) the common symptom is loss of memory. Learning and memory are associated with amoeboid movements of synaptic endings. There are numerous indications that aberrant plasticity is critically involved in Alzheimer’s. Synaptic membranes share the highest content of docosahexaenoic acid (DHA) of all cell membranes; moreover, synapse density is reduced in ageing as well as levels of DHA. On the other hand, epidemiological studies suggest that consumption of DHA is associated with a reduced incidence of AD. Is this neuroprotective action the result of refilling DHA into membranes? Is the prosurvival effect due to a more selective signalling by a DHA-derived mediator? Neuroprotecting D1 (NPD1) is a newly identified DHA-derived messenger, which protects synapses and decreases the number of activated microglia in the hippocampal system. Since NPD1 exhibits neuroprotective activity against beta-amyloid, represses apoptosis, and promotes the expression of antiapoptotic genes, DHA protection in cells in culture and in vivo models may involve NPD1 synthesis. Delaying AD onset by a few years would reduce the number of the cases of dementia in the community. The authors – in view of the increased neuroinflammatory reaction frequently observed during normal brain ageing - suggest the long-term use of “fatty aspirin”, an association of DHA and aspirin, to postpone, or prevent, the structural neurodegeneration of the brain.