Neurochemical Research

, Volume 25, Issue 9, pp 1161-1172

First online:

The Endosomal-Lysosomal System of Neurons in Alzheimer's Disease Pathogenesis: A Review

  • Ralph A. NixonAffiliated withNathan Kline InstituteDepartments of Psychiatry and Cell Biology New York, University School of Medicine
  • , Anne M. CataldoAffiliated withNathan Kline InstituteMcLean Hospital, Harvard Medical School
  • , Paul M. MathewsAffiliated withNathan Kline InstituteDepartments of Psychiatry

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A prominent feature of brain pathology in Alzheimer's disease is a robust activation of the neuronal lysosomal system and major cellular pathways converging on the lysosome, namely, endocytosis and autophagy. Recent studies that identify a disturbance of the endocytic pathway as one of the earliest known manifestation of Alzheimer's disease provide insight into how β-amyloidogenesis might be promoted in sporadic Alzheimer's disease, the most prevalent and least well understood form of the disease. Primary lysosomal dysfunction has historically been linked to neurodegeneration. New data now directly implicate cathepsins as proteases capable of initiating, as well as executing, cell death programs in certain pathologic states. These and other studies support the view that the progressive alterations of lysosomal function observed during aging and Alzheimer's disease contribute importantly to the neurodegenerative process in Alzheimer's disease.

Proteases cathepsin D apoptosis β-amyloid amyloid precursor protein