Abstract
Alzheimer’s disease (AD) represents one of the most dramatic threats to healthy aging and devising effective treatments for this devastating condition remains a major challenge in biomedical research. Much has been learned about the molecular concepts that govern proteolytic processing of the amyloid precursor protein to amyloid-β peptides (Aβ), and how accelerated accumulation of neurotoxic Aβ peptides underlies neuronal cell death in rare familial but also common sporadic forms of this disease. Out of a plethora of proposed modulators of amyloidogenic processing, one protein emerged as a key factor in AD pathology, a neuronal sorting receptor termed SORLA. Independent approaches using human genetics, clinical pathology, or exploratory studies in animal models all converge on this receptor that is now considered a central player in AD-related processes by many. This review will provide a comprehensive overview of the evidence implicating SORLA-mediated protein sorting in neurodegenerative processes, and how receptor gene variants in the human population impair functional receptor expression in sporadic but possibly also in autosomal-dominant forms of AD.
Highlights
Alzheimer’s disease (AD) represents one of the most dramatic threats to healthy aging in all societies and devising effective treatments for this devastating condition remains a major challenge in biomedical research
Much has been learned about the molecular concepts that govern proteolytic processing of the amyloid precursor protein (APP) to amyloid-β peptides (Aβ), and how accelerated accumulation of neurotoxic Aβ peptides causes neurodegeneration in rare familial and common sporadic forms of AD
Out of a plethora of proposed modulators of APP processing, one protein emerges as a promising candidate in AD pathology, a sorting receptor called sorting-related receptor with A-type repeats (SORLA)
Summary
Alzheimer’s disease (AD) represents one of the most dramatic threats to healthy aging in all societies and devising effective treatments for this devastating condition remains a major challenge in biomedical research. A novel secretase activity, termed η-secretase, has been identified that acts on the APP precursor polypeptide (panel b in the figure) [99] This protease produces a carboxyl terminal stub CTFη that serves as alternative substrate to α- and β-secretases in non-amyloidogenic and amyloidogenic processing, respectively. Evidence that the extent of breakdown of APP to Aβ determines onset and progression of AD stems from rare autosomal dominant, early onset forms of AD caused by mutations in the genes encoding APP or in presenilin-1 or -2 (PSEN1, PSEN2), subunits of the γ-secretase complex These mutations are typically associated with an overall increase in the production of Aβ or with a shift towards generation of the more disease-prone variant Aβ42 [45]. Many of them are believed to act through enhancing the accumulation and neurotoxic action of Aβ
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