Lysosomal system pathways: genes to neurodegeneration in Alzheimer's disease

J Alzheimers Dis. 2006;9(3 Suppl):277-89. doi: 10.3233/jad-2006-9s331.


The identification of cathepsins in amyloid-beta plaques revealed broad dysfunction of the lysosomal system in Alzheimer's disease (AD). Coinciding with the discovery that proteolysis is required to generate the Abeta-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology*
  • Amyloid beta-Protein Precursor / metabolism
  • Cell Death / physiology
  • Endocytosis / physiology
  • Genes / genetics*
  • Humans
  • Lysosomes / physiology*
  • Nerve Degeneration / genetics*
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / pathology*


  • Amyloid beta-Protein Precursor