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      Amyloid precursor protein and endosomal–lysosomal dysfunction in Alzheimer’s disease: inseparable partners in a multifactorial disease

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          Abstract

          Abnormalities of the endosomal–lysosomal network (ELN) are a signature feature of Alzheimer’s disease (AD). These include the earliest known cytopathology that is specific to AD and that affects endosomes and induces the progressive failure of lysosomes, each of which are directly linked by distinct mechanisms to neurodegeneration. The origins of ELN dysfunction and β-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 β-amyloidogenesis in AD (APP, PSEN1/2, and APOE4) have primary effects on ELN function. The importance of primary ELN dysfunction to pathogenesis is underscored by the mutations in more 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 β-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-β, 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 in Alzheimer’s disease: inseparable partners in a multifactorial disease.

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          Author and article information

          Journal
          FASEB J
          FASEB J
          fasebj
          fasebj
          fasebj
          The FASEB Journal
          Federation of American Societies for Experimental Biology (Bethesda, MD, USA )
          0892-6638
          1530-6860
          July 2017
          14 June 2017
          14 June 2017
          : 31
          : 7
          : 2729-2743
          Affiliations
          Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, New York, USA;
          Department of Psychiatry and Department of Cell Biology, New York University Langone Medical Center, New York, New York, USA
          Author notes
          [ 1 ]Correspondence: New York University School of Medicine, New York, NY 10016, USA. E-mail: ralph.nixon@ 123456nki.rfmh.org
          Article
          PMC6137496 PMC6137496 6137496 FJ_201700359
          10.1096/fj.201700359
          6137496
          28663518
          © FASEB
          Page count
          Figures: 3, Tables: 0, Equations: 0, References: 217, Pages: 15
          Categories
          Alzheimer’s Disease Review Series
          Review-Article
          Custom metadata
          v1

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