Alzheimer’s Disease Risk Genes and Mechanisms of Disease Pathogenesis

Accumulations of insoluble deposits of amyloid β-peptide are major pathological hallmarks of Alzheimer disease. Amyloid β-peptide is derived by sequential proteolytic processing from a large type I trans-membrane protein, the β-amyloid precursor protein. The proteolytic enzymes involved in its processing are named secretases. β- and γ-secretase liberate by sequential cleavage the neurotoxic amyloid β-peptide, whereas α-secretase prevents its generation by cleaving within the middle of the amyloid domain. In this chapter we describe the cell biological and biochemical characteristics of the three secretase activities involved in the proteolytic processing of the precursor protein. In addition we outline how the precursor protein maturates and traffics through the secretory pathway to reach the subcellular locations where the individual secretases are preferentially active. Furthermore, we illuminate how neuronal activity and mutations which cause familial Alzheimer disease affect amyloid β-peptide generation and therefore disease onset and progression.

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Trafficking and Proteolytic Processing of APP

An important pathological feature of Alzheimer's disease (AD) is the presence of extracellular senile plaques in the brain. Senile plaques are composed of aggregations of small peptides called β-amyloid (Aβ). Multiple lines of evidence demonstrate that overproduction/aggregation of Aβ in the brain is a primary cause of AD and inhibition of Aβ generation has become a hot topic in AD research. Aβ is generated from β-amyloid precursor protein (APP) through sequential cleavages first by β-secretase and then by γ-secretase complex. Alternatively, APP can be cleaved by α-secretase within the Aβ domain to release soluble APPα and preclude Aβ generation. Cleavage of APP by caspases may also contribute to AD pathologies. Therefore, understanding the metabolism/processing of APP is crucial for AD therapeutics. Here we review current knowledge of APP processing regulation as well as the patho/physiological functions of APP and its metabolites.

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APP processing in Alzheimer's disease

Summary The β secretase, widely known as β-site amyloid precursor protein cleaving enzyme 1 (BACE1), initiates the production of the toxic amyloid β (Aβ) that plays a crucial early part in Alzheimer's disease pathogenesis. BACE1 is a prime therapeutic target for lowering cerebral Aβ concentrations in Alzheimer's disease, and clinical development of BACE1 inhibitors is being intensely pursued. Although BACE1 inhibitor drug development has proven challenging, several promising BACE1 inhibitors have recently entered human clinical trials. The safety and efficacy of these drugs are being tested at present in healthy individuals and patients with Alzheimer's disease, and will soon be tested in individuals with presymptomatic Alzheimer's disease. Although hopes are high that BACE1 inhibitors might be efficacious for the prevention or treatment of Alzheimer's disease, concerns have been raised about potential mechanism-based side-effects of these drugs. The potential of therapeutic BACE1 inhibition might prove to be a watershed in the treatment of Alzheimer's disease.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(13)70276-X.pdf

Targeting the β secretase BACE1 for Alzheimer's disease therapy

Amyloid precursor protein (APP) gives rise to the amyloid-β peptide and thus has a key role in the pathogenesis of Alzheimer disease. By contrast, the physiological functions of APP and the closely related APP-like proteins (APLPs) remain less well understood. Studying these physiological functions has been challenging and has required a careful long-term strategy, including the analysis of different App-knockout and Aplp-knockout mice. In this Review, we summarize these findings, focusing on the in vivo roles of APP family members and their processing products for CNS development, synapse formation and function, brain injury and neuroprotection, as well as ageing. In addition, we discuss the implications of APP physiology for therapeutic approaches.

Not just amyloid: physiological functions of the amyloid precursor protein family

The amyloid precursor protein (APP) undergoes constitutive shedding by a protease activity called α-secretase. This is considered an important mechanism preventing the generation of the Alzheimer's disease amyloid-β peptide (Aβ). α-Secretase appears to be a metalloprotease of the ADAM family, but its identity remains to be established. Using a novel α-secretase-cleavage site-specific antibody, we found that RNAi-mediated knockdown of ADAM10, but surprisingly not of ADAM9 or 17, completely suppressed APP α-secretase cleavage in different cell lines and in primary murine neurons. Other proteases were not able to compensate for this loss of α-cleavage. This finding was further confirmed by mass-spectrometric detection of APP-cleavage fragments. Surprisingly, in different cell lines, the reduction of α-secretase cleavage was not paralleled by a corresponding increase in the Aβ-generating β-secretase cleavage, revealing that both proteases do not always compete for APP as a substrate. Instead, our data suggest a novel pathway for APP processing, in which ADAM10 can partially compete with γ-secretase for the cleavage of a C-terminal APP fragment generated by β-secretase. We conclude that ADAM10 is the physiologically relevant, constitutive α-secretase of APP.

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ADAM10 is the physiologically relevant, constitutive α-secretase of the amyloid precursor protein in primary neurons

Constitutive α- and β-secretase cleavages of the amyloid precursor protein are partially coupled in neurons, but not in frequently used cell lines.

The transmembrane protein, ADAM10 (a disintegrin and metalloprotease 10), has key physiologic functions—for example, during embryonic development and in the brain During transit through the secretory pathway, immature ADAM10 (proADAM10) is converted into its proteolytically active, mature form (mADAM10) Increasing or decreasing the abundance and/or activity of mADAM10 is considered to be a therapeutic approach for the treatment of such diseases as Alzheimer’s disease and cancer Yet biochemical detection and characterization of mADAM10 has been difficult In contrast, proADAM10 is readily detected—for example, in immunoblots—which suggests that mADAM10 is only a fraction of total cellular ADAM10 Here, we demonstrate that mADAM10, but not proADAM10, unexpectedly undergoes rapid, time-dependent degradation upon biochemical cell lysis in different cell lines and in primary neurons, which prevents the detection of the majority of mADAM10 in immunoblots This degradation required the catalytic activity of A

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fj.201700823RR

Huanhuan Wang

Papers

ADAM10 is the physiologically relevant, constitutive α-secretase of the amyloid precursor protein in primary neurons

Constitutive α- and β-secretase cleavages of the amyloid precursor protein are partially coupled in neurons, but not in frequently used cell lines.

The metalloprotease ADAM10 (a disintegrin and metalloprotease 10) undergoes rapid, postlysis autocatalytic degradation.