Affiliations: [a] Nathan Kline Institute, Orangeburg, NY, USA | [b] Department of Psychiatry, New York University School of Medicine, New York, NY, USA | [c] Department of Cell Biology, New York University School of Medicine, New York, NY, USA | [d] Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA
Correspondence:
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Correspondence to: Ralph A. Nixon, Ph.D., M.D., Center for Dementia Research, Nathan Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA. Tel.: +1 845 398 5423; Fax: +1 845 398 5422; E-mail: nixon@nki.rfmh.org
Abstract: Robust activation of the neuronal lysosomal system and cellular pathways converging on the lysosome, such as the endocytic and autophagic pathways, are prominent neuropathological features of Alzheimer's disease. Disturbances of the neuronal endocytic pathway, which are one of the earliest known intracellular changes occurring in Alzheimer's disease and Down syndrome, provide insight into how ß-amyloidogenesis might be promoted in sporadic Alzheimer's disease, the most prevalent and least well understood form of the disease. Primary lysosomal system dysfunction in inherited disorders is commonly associated with prominent neurological phenotypes and neurodegeneration. New studies now directly implicate lysosomal cathepsins as proteases capable of initiating, as well as executing, cell death programs. These and other studies support the view that the progressive alterations of lysosomal system function in Alzheimer's disease have broad relevance to the neurodegenerative processes occurring during the disease.
