Affiliations: [a] Center for Dementia Research, Nathan S. Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA | [b] Department of Psychiatry, New York University, 550 First Ave, New York, NY 10016, USA | [c] Department of Cell Biology, New York University, 550 First Ave, New York, NY 10016, USA | [d] Mailman Research Center, McLean Hospital, Harvard University, 115 Mill Street, Belmont, MA 02478, USA
Correspondence:
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Corresponding author: Dr. Ralph Nixon, Ph.D., M.D. Nathan Kline Institute, New York University School of Medicine, 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: The identification of cathepsins in amyloid-β plaques revealed broad dysfunction of the lysosomal system in Alzheimer's disease (AD). Coinciding with the discovery that proteolysis is required to generate the Aβ-peptide, these findings heralded an era of intense investigation on proteases in neurodegeneration. This review traces lysosomal system pathology from its early characterization to its origins within two pathways leading to the lysosome, the endocytic and autophagic pathways. An understanding has grown about how these two pathways are adversely influenced by normal brain aging and by genetic and environmental risk factors for AD, resulting in increased susceptibility of neurons to injury, amyloidogenesis, and neurodegeneration.
