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Despite decades of intense research, therapeutics for Alzheimer's disease (AD) are still limited to symptomatic treatments that possess only short-term efficacy. Recently, several large-scale Phase III trials targeting amyloid-β production or clearance have failed to show efficacy, leading to a reexamination of the amyloid hypothesis as well as highlighting the need to explore alternatives in both clinical testing strategies and drug discovery targets. In this review, we discuss therapeutics currently being tested in clinical trials and up-and-coming interventions that have shown promise in animal models, devoting attention to the mechanisms that may underlie their ability to influence disease progression and placing particular emphasis on tau therapeutics. [ABSTRACT FROM AUTHOR]

Aggregation and accumulation of Aβ42 play an initiating role in Alzheimer's disease (AD); thus, selective lowering of Aβ42 by γ-secretase modulators (GSMs) remains a promising approach to AD therapy. Based on evidence suggesting that steroids may influence Aβ production, we screened 170 steroids at 10 µM for effects on Aβ42 secreted from human APP-overexpressing Chinese hamster ovary cells. Many acidic steroids lowered Aβ42, whereas many nonacidic steroids actually raised Aβ42. Studies on the more potent compounds showed that Aβ42-lowering steroids were bonafide GSMs and Aβ42-raising steroids were inverse GSMs. The most potent steroid GSM identified was 5β-cholanic acid (EC50=5.7 µM; its endogenous analog lithocholic acid was virtually equipotent), and the most potent inverse GSM identified was 4-androsten-3-one-17β-carboxylic acid ethyl ester (EC50=6.25 µM). In addition, we found that both estrogen and progesterone are weak inverse GSMs with further complex effects on APP processing. These data suggest that certain endogenous steroids may have the potential to act as GSMs and add to the evidence that cholesterol, cholesterol metabolites, and other steroids may play a role in modulating Aβ production and thus risk for AD. They also indicate that acidic steroids might serve as potential therapeutic leads for drug optimization/development. [ABSTRACT FROM AUTHOR]

Our understanding of Alzheimer's disease pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic form of the disease. It may be possible to overcome these challenges by reprogramming primary cells from patients into induced pluripotent stem cells (iPSCs). Here we reprogrammed primary fibroblasts from two patients with familial Alzheimer's disease, both caused by a duplication of the amyloid-? precursor protein gene (APP; termed APPDp), two with sporadic Alzheimer's disease (termed sAD1, sAD2) and two non-demented control individuals into iPSC lines. Neurons from differentiated cultures were purified with fluorescence-activated cell sorting and characterized. Purified cultures contained more than 90% neurons, clustered with fetal brain messenger RNA samples by microarray criteria, and could form functional synaptic contacts. Virtually all cells exhibited normal electrophysiological activity. Relative to controls, iPSC-derived, purified neurons from the two APPDp patients and patient sAD2 exhibited significantly higher levels of the pathological markers amyloid-?(1-40), phospho-tau(Thr?231) and active glycogen synthase kinase-3? (aGSK-3?). Neurons from APPDp and sAD2 patients also accumulated large RAB5-positive early endosomes compared to controls. Treatment of purified neurons with ?-secretase inhibitors, but not ?-secretase inhibitors, caused significant reductions in phospho-Tau(Thr?231) and aGSK-3? levels. These results suggest a direct relationship between APP proteolytic processing, but not amyloid-?, in GSK-3? activation and tau phosphorylation in human neurons. Additionally, we observed that neurons with the genome of one sAD patient exhibited the phenotypes seen in familial Alzheimer's disease samples. More generally, we demonstrate that iPSC technology can be used to observe phenotypes relevant to Alzheimer's disease, even though it can take decades for overt disease to manifest in patients. [ABSTRACT FROM AUTHOR]

The amyloid precursor protein (APP) plays a central role in the pathophysiology of Alzheimer's disease in large part due to the sequential proteolytic cleavages that result in the generation of β-amyloid peptides (Aβ). Not surprisingly, the biological properties of APP have also been the subject of great interest and intense investigations. Since our 2006 review, the body of literature on APP continues to expand, thereby offering further insights into the biochemical, cellular and functional properties of this interesting molecule. Sophisticated mouse models have been created to allow in vivo examination of cell type-specific functions of APP together with the many functional domains. This review provides an overview and update on our current understanding of the pathobiology of APP. [ABSTRACT FROM AUTHOR]

Increasing biochemical and genetic evidence indicates that the amyloid-β (Aβ) peptide derived from amyloid precursor protein (APP) plays a central role in Alzheimer's disease (AD) pathogenesis. We previously reported that RanBP9 promotes Aβ generation by scaffolding APP/BACE1/LRP complexes together. Interestingly, the RanBP9-Δ1/N60 (residues 1-392) deletion mutant interacted much more strongly with APP/BACE1/LRP than full-length RanBP9. In this study, we found that RanBP9-N60, a processed form of RanBP9 virtually identical to the RanBP9-Δ1/N60 mutant, was strongly increased in AD brains compared with controls. To evaluate the potential pathogenic consequences of this phenotype, we studied the differential biological properties of full-length RanBP9 vs. RanBP9-Δ1/N60 in HEK293T and Neuro-2A cells. The RanBP9-Δ1/N60 fragment, which lacks a nuclear localization signal, displayed enhanced cytoplasmic vs. nuclear localization and >3-fold enhanced stability than full-length RanBP9. Importantly, RanBP9-Δ1/N60, which contains the LisH dimerization domain, retained the capacity to form self-interacting multimeric complexes and increased AΒ generation by ∼5-fold over vector controls, more potent than the ∼3-fold increase seen by full-length RanBP9. Taken together, these data indicate that RanBP9-N60 may further drive the amyloid cascade in AD and that the proteolytic processing of RanBP9 may be an attractive therapeutic target. [ABSTRACT FROM AUTHOR]

The Swedish mutation within the amyloid precursor protein (APP) causes early-onset Alzheimer’s disease due to increased cleavage of APP by BACE1. While β-secretase shedding of Swedish APP (APPswe) largely results from an activity localized in the late secretory pathway, cleavage of wild-type APP occurs mainly in endocytic compartments. However, we show that liberation of Aβ from APPswe is still dependent on functional internalization from the cell surface. Inspite the unchanged overall β-secretase cleaved soluble APP released from APPswe secretion, mutations of the APPswe internalization motif strongly reduced C99 levels and substantially decreased Aβ secretion. We point out that α-secretase activity-mediated conversion of C99 to C83 is the main cause of this Aβ reduction. Furthermore, we demonstrate that α-secretase cleavage of C99 even contributes to the reduction of Aβ secretion of internalization deficient wild-type APP. Therefore, inhibition of α-secretase cleavage increased Aβ secretion through diminished conversion of C99 to C83 in APP695, APP695swe or C99 expressing cells. [ABSTRACT FROM AUTHOR]

In addition to the proteolytic cleavages that give rise to amyloid-beta (Abeta), the amyloid-beta protein precursor (AbetaPP) is cleaved at Asp664 intracytoplasmically. This cleavage releases a cytotoxic peptide, APP-C31, removes AbetaPP-interaction motifs required for signaling and internalization, and is required for the generation of AD-like deficits in a mouse model of the disease. Although we and others had previously shown that Asp664 cleavage of AbetaPP is increased in AD brains, the distribution of the Asp664-cleaved forms of AbetaPP in non-diseased and AD brains at different ages had not been determined. Confirming previous reports, we found that Asp664-cleaved forms of AbetaPP were increased in neuronal cytoplasm and nuclei in early-stage AD brains but were absent in age-matched, non-diseased control brains and in late-stage AD brains. Remarkably, however, Asp664-cleaved AbetaPP was prominent in neuronal somata and in processes in entorhinal cortex and hippocampus of non-diseased human brains at ages <45 years. Our observations suggest that Asp664 cleavage of AbetaPP may be part of the normal proteolytic processing of AbetaPP in young (<45 years) human brain and that this cleavage is down-regulated with normal aging, but is aberrantly increased and altered in location in early AD. [ABSTRACT FROM AUTHOR]

The major defining pathological hallmark of Alzheimer's disease (AD) is the accumulation of amyloid β protein (Aβ), a small peptide derived from β- and γ-secretase cleavages of the amyloid precursor protein (APP). Recent studies have shown that β- and γ-secretase activities of BACE1 and presenilin, respectively, are concentrated in intracellular lipid raft microdomains. However, the manner in which APP normally traffics to lipid rafts is unknown. In this study, using transient transfection and immuno-precipitation assays, we show that the cytoplasmic domain of low-density lipoprotein receptor-related protein (LRP) interacts with APP and increases Aβ secretion and APP β-CTF (C-terminal fragment) generation by promoting BACE1-APP interaction. We also employed discontinuous sucrose density gradient ultracentrifugation to show that the LRP cytoplasmic domain-mediated effect was accompanied by greatly increased localization of APP and BACE1 to lipid raft membranes, where β- and γ-secretase activities are highly enriched. Moreover, we provide evidence that endogenous LRP is required for the normal delivery of APP to lipid rafts and Aβ generation primarily in the endocytic but not secretory pathway. These results may provide novel insights to block Aβ generation by targeting LRP-mediated delivery of APP to raft microdomains. [ABSTRACT FROM AUTHOR]

Synaptic dysfunction has been shown to be one of the earliest correlates of disease progression in animal models of Alzheimer's disease. Amyloid-β protein (Aβ) is thought to play an important role in disease-related synaptic dysfunction, but the mechanism by which Aβ leads to synaptic dysfunction is not understood. Here we describe evidence that cleavage of APP in the C terminus may be necessary for the deficits present in APP transgenic mice. In APP transgenic mice with a mutated cleavage site at amino acid 664, normal synaptic transmission, synaptic plasticity, and learning were maintained despite the presence of elevated levels of APP, Aβ42, and even plaque accumulation. These results indicate that cleavage of APP may play a critical role in the development of synaptic and behavioral dysfunction in APP transgenic mice. [ABSTRACT FROM AUTHOR]

Certain non-steroidal anti-inflammatory drugs (NSAIDs) preferentially inhibit production of the amyloidogenic Aβ42 peptide, presumably by direct modulation of γ-secretase activity. A recent report indicated that NSAIDs could reduce Aβ42 by inhibition of the small GTPase Rho, and a single inhibitor of Rho kinase (ROCK) mimicked the effects of Aβ42-lowering NSAIDs. To investigate whether Aβ42 reduction is a common property of ROCK inhibitors, we tested commercially available compounds in cell lines that were previously used to demonstrate the Aβ42-lowering activity of NSAIDs. Surprisingly, we found that two ROCK inhibitors reduced total Aβ secretion in a dose-dependent manner but showed no selectivity for Aβ42. In addition, ROCK inhibitors did not increase Aβ38 secretion in cell-based assays or reduce Aβ production in γ-secretase in vitro assays, which are critical characteristics of Aβ42-lowering NSAIDs. The reduction in total Aβ levels by ROCK inhibitors was not accompanied by overall-changes in amyloid precursor protein processing. Targeting ROCK by expression of dominant-negative or constitutively active ROCK mutants failed to modulate Aβ secretion, indicating that ROCK inhibition may either be redundant or insufficient for Aβ reduction by ROCK inhibitors. Taken together, these results seem to exclude a mechanistic involvement of ROCK in the Aβ42-lowering activity of NSAIDs. [ABSTRACT FROM AUTHOR]

The amyloid precursor protein (APP) takes a central position in Alzheimer's disease (AD) pathogenesis: APP processing generates the β-amyloid (Aβ) peptides, which are deposited as the amyloid plaques in brains of AD individuals; Point mutations and duplications of APP are causal for a subset of early onset of familial Alzheimer's disease (FAD). Not surprisingly, the production and pathogenic effect of Aβ has been the central focus in AD field. Nevertheless, the biological properties of APP have also been the subject of intense investigation since its identification nearly 20 years ago as it demonstrates a number of interesting putative physiological roles. Several attractive models of APP function have been put forward recently based on in vitro biochemical studies. Genetic analyses of gain- and loss-of-function mutants in Drosophila and mouse have also revealed important insights into its biological activities in vivo. This article will review the current understanding of APP physiological functions. [ABSTRACT FROM AUTHOR]

Increased Aß42 production has been linked to the development of Alzheimer disease. We now identify a number of compounds that raise Aß42. Among the more potent Aß42-raising agents identified are fenofibrate, an antilipidemic agent, and celecoxib, a COX-2-selective NSAID. Many COX-2-selective NSAIDs tested raised Aß42, including multiple COX-2-selective derivatives of two Aß42-lowering NSAIDs. Compounds devoid of COX activity and the endogenous isoprenoids FPP and GGPP also raised Aß42. These compounds seem to target the?-secretase complex, increasing?-secretase-catalyzed production of Aß42 in vitro. Short-term in vivo studies show that two Aß42-raising compounds increase Aß42 levels in the brains of mice. The elevations in Aß42 by these compounds are comparable to the increases in Aß42 induced by Alzheimer disease-causing mutations in the genes encoding amyloidßprotein precursor and presenilins, raising the possibility that exogenous compounds or naturally occurring isoprenoids might increase Aß42 production in humans. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases can be genetic or sporadic in origin. Genetic analysis has changed the study of the pathogenesis of these disorders by showing the causative functions of rare mutations. Yet, in the most common age-associated neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, the causes of neurodegeneration remain to be clarified. The observations that presenilin modulates proteolysis and turnover of several signaling molecules have led to speculations that pathways that are important in development may contribute to neurodegeneration. In this article, the possibility that these presenilin-regulated molecules may contribute to neurodegeneration is reviewed. INSET: GLOSSARY. [ABSTRACT FROM AUTHOR]

The amyloid β-protein precursor (APP) is proteolytically cleaved to generate the amyloid β-protein (Aβ), the principal constituent of senile plaques found in Alzheimer's disease (AD). In addition, Aβ in its oligomeric and fibrillar forms have been hypothesized to induce neuronal toxicity. We and others have previously shown that APP can be cleaved by caspases at the C-terminus to generate a potentially cytotoxic peptide termed C31. Furthermore, this cleavage event and caspase activation were increased in the brains of AD, but not control, cases. In this study, we show that in cultured cells, Aβ induces caspase cleavage of APP in the C-terminus and that the subsequent generation of C31 contributes to the apoptotic cell death associated with Aβ. Interestingly, both Aβ toxicity and C31 pathway are dependent on the presence of APP. Both APP-dependent Aβ toxicity and C31-induced apoptotic cell death involve apical or initiator caspases-8 and -9. Our results suggest that Aβ-mediated toxicity initiates a cascade of events that includes caspase activation and APP cleavage. These findings link C31 generation and its potential cell death activity to Aβ cytotoxicity, the leading mechanism proposed for neuronal death in AD. [ABSTRACT FROM AUTHOR]

The β-amyloid precursor protein has been the focus of much attention from the Alzheimer's disease community for the past decade and a half. The β-amyloid precursor protein holds a pivotal position in Alzheimer's disease research because it is the precursor to the amyloid β-protein which many believe plays a central role in Alzheimer's disease pathogenesis. It was also the first gene in which mutations associated with inherited Alzheimer's disease were found. Although the molecular details of the generation of amyloid β-protein from β-amyloid precursor protein are being unraveled, the actual physiological functions of β-amyloid precursor protein are far from clear. This situation is changing as accumulating new evidence suggests that the C-terminal cytosolic tail of β-amyloid precursor protein may have multiple biological activities, ranging from axonal transport to nuclear signaling. This article reviews the current state of knowledge about the biological functions of β-amyloid precursor protein . [ABSTRACT FROM AUTHOR]

The low-density lipoprotein receptor-related protein (LRP) has recently been implicated in numerous intracellular signaling functions, as well as in Alzheimer's disease pathogenesis. Studies have shown that the β-amyloid precursor protein (APP) interacts with LRP and that this association may impact the production of amyloid β-protein (Aβ). In this report, we provide evidence that LRP regulates trafficking of intracellular proteins independently of its lipoprotein receptor functions. We show that in the absence of LRP, Aβ production, APP secretion, APP internalization, turnover of full-length APP and stability of APP C-terminal fragments are affected. Importantly, these changes are not APP isoform dependent. Using deletion constructs, the critical region in LRP that modulates APP processing was mapped to a seven peptide domain around the second NPXY domain (residues 4504-4510). Therefore, we propose a model by which LRP functionally modulates APP processing, including those steps critical for Aβ production, through interactions of the cytosolic domains. [ABSTRACT FROM AUTHOR]

Abstract The synapse loss and neuronal cell death characteristic of Alzheimer's disease (AD) are believed to result in large part from the neurotoxic effects of β-amyloid peptide (Aβ), a 40–42 amino acid peptide(s) derived proteolytically from β-amyloid precursor protein (APP). However, APP is also cleaved intracellularly to generate a second cytotoxic peptide, C31, and this cleavage event occurs in vivo as well as in vitro and preferentially in the brains of AD patients ( Lu et al. 2000 ). Here we show that APPC31 is toxic to neurons in primary culture, and that like APP, the APP family members APLP1 and possibly APLP2 are cleaved by caspases at their C-termini. The carboxy-terminal peptide derived from caspase cleavage of APLP1 shows a degree of neurotoxicity comparable to APPC31. Our results suggest that even though APLP1 and APLP2 cannot generate Aβ, they may potentially contribute to the pathology of AD by generating peptide fragments whose toxicity is comparable to that of APPC31. [ABSTRACT FROM AUTHOR]

Examines the role of aspartate-257 of prenisilin 1 (PS1) on mouse development and production of Β-amyloid peptides via Β-catenin-independent mechanisms. Generation of transgenic mice; Gene expression of PS1; Use of Westen blotting an immunoprecipitation methods; List of the rescue phenotypes by transgenes.

Reports the beneficial effects of nonsteroidal anti-inflammatory drugs (NSAID). Reduction of the occurrence of Alzheimer's disease; Reaction of NSAID to Abeta42 peptide; Impact of the drugs to the amyloid pathology in the brain.

Examines the association between loss of presenilin (PS1) and enhanced beta-catenin protein during the development of Alzheimer's disease. Importance of PS1 in controlling epidermal cell proliferation; Expression of PS1 transgene during the development of skin cancers.