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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Kominami, E. Cataldo, A. M. Paskevich, P. A. Nixon, R. A. |
| Description | Author Affiliation: Cataldo AM ( Laboratories for Molecular Neuroscience, McLean Hospital, Belmont, MA.); |
| Abstract | beta-Amyloid formation requires multiple abnormal proteolytic cleavages of amyloid precursor protein (APP), including one within its intramembrane domain. Lysosomes, which contain a wide variety of proteases (cathepsins) and other acid hydrolases, are major sites for the turnover of membrane proteins and other cell constituents. Using immunocytochemistry, immunoelectron microscopy, and enzyme histochemistry, we studied the expression and cellular distributions of 10 lysosomal hydrolases, including 4 cathepsins, in neocortex from patients with Alzheimer disease and control (non-Alzheimer-disease) individuals. In control brains, acid hydrolases were localized exclusively to intracellular lysosome-related compartments, and 8 of the 10 enzymes predominated in neurons. In Alzheimer disease brains, strongly immunoreactive lysosomes and lipofuscin granules accumulated markedly in the perikarya and proximal dendrites of many cortical neurons, some of which were undergoing degeneration. More strikingly, these same hydrolases were present in equally high or higher levels in senile plaques in Alzheimer disease, but they were not found extracellularly in control brains, including those from Parkinson or Huntington disease patients. At the ultrastructural level, hydrolase immunoreactivity in senile plaques was localized to extracellular lipofuscin granules similar in morphology to those within degenerating neurons. Two cathepsins that were undetectable in neurons were absent from senile plaques. These results show that lysosome function is altered in cortical neurons in Alzheimer disease. The presence of a broad spectrum of acid hydrolases in senile plaques indicates that lysosomes and their contents may be liberated from cells, principally neurons and their processes, as they degenerate. Because cathepsins can cleave polypeptide sites on APP relevant for beta-amyloid formation, their abnormal extracellular localization and dysregulation in Alzheimer disease can account for the multiple hydrolytic events in beta-amyloid formation. The actions of membrane-degrading acid hydrolases could also explain how the intramembrane portion of APP containing the C terminus of beta-amyloid becomes accessible to proteases. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 24 |
| Volume Number | 88 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 1991-01-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Alzheimer Disease Enzymology Brain Hydrolases Lysosomes Pathology Amyloid Beta-Peptides Astrocytes Cathepsins Huntington Disease Ultrastructure Neurons Parkinson Disease Reference Values Alpha-Glucosidases Beta-N-Acetylhexosaminidases Research Support, U.S. Gov't, P.H.S. Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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