Amyloid precursor protein & endosomal-lysosomal dysfunction in Alzheimer's disease: Inseparable partners in a multifactorial disease

Abstract

Abnormalities of the endosomal-lysosomalnetwork (ELN) are a signature feature ofAlzheimer'sdisease (AD). These include the earliest known cytopathology that is specific toADand that affects endosomes and induces the progressive failure of lysosomes, each of which are directly linked by distinct mechanisms to neurodegeneration. The origins of ELNdysfunction andb-Amyloidogenesis closely overlap,which reflects their common genetic basis, the established early involvement of endosomes and lysosomes in amyloid precursor protein (APP) processing and clearance, and the pathologic effect of certain APP metabolites on ELN functions. Genes that promote b-Amyloidogenesis in AD (APP, PSEN1/2, and APOE4) have primary effects on ELN function. The importance of primary ELNdysfunction to pathogenesis is underscored by themutations inmore than 35 ELN-related genes that, thus far, are known to cause familial neurodegenerative diseases even though different pathogenic proteins may be involved. In this article, I discuss growing evidence that implicates AD gene-driven ELN disruptions as not only the antecedent pathobiology that underlies b-Amyloidogenesis but also as the essential partner with APP and its metabolites that drive the development of AD, including tauopathy, synaptic dysfunction, and neurodegeneration. The striking amelioration of diverse deficits in animal AD models by remediating ELN dysfunction further supports a need to integrate APP and ELN relationships, including the role of amyloid-b, into a broader conceptual framework of how AD arises, progresses, and may be effectively therapeutically targeted.-Nixon, R.A.Amyloid precursor protein and endosomal-lysosomal dysfunction inAlzheimer's disease: inseparable partners in a multifactorial disease. FASEB J. 31, 2729-2743 (2017). www.fasebj.org.