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Intraneuronal Abeta42 accumulation in human brain.
G K Gouras1, J Tsai, J Naslund
1Laboratory of Molecular and Cellular Neuroscience and Fisher Center for Research on Alzheimer's Disease, The Rockefeller University New York, New York 10021, USA. gkgouras@mail.med.cornell.edu
The American Journal of Pathology
|January 7, 2000
Summary
Intracellular accumulation of beta-amyloid 42 (Abeta42) in neurons precedes Alzheimer
Area of Science:
- Neuroscience
- Pathology
- Biochemistry
Background:
- Alzheimer's disease (AD) is marked by senile plaques (SPs) and neurofibrillary tangles (NFTs).
- Beta-amyloid (Abeta) peptides, particularly Abeta42, are central to AD pathophysiology.
- Genetic mutations linked to AD increase Abeta secretion, especially Abeta42.
Purpose of the Study:
- To investigate whether extracellular Abeta deposition or intracellular Abeta accumulation initiates Alzheimer's disease.
- To determine the timing of Abeta42 accumulation relative to NFT and plaque formation.
Main Methods:
- Confocal immunofluorescence microscopy was used to detect endogenous Abeta42.
- Immunohistochemical analysis was performed on human neurons in AD-vulnerable brain regions.
- Studies included neurons from PS1 mutant transgenic mice.
Main Results:
- Human neurons in AD-vulnerable brain regions show accumulation of gamma-cleaved Abeta42.
- Intraneuronal Abeta42 immunoreactivity appears before neurofibrillary tangle and Abeta plaque deposition.
- Endogenous Abeta42 was detected within neurons of PS1 mutant mice.
Conclusions:
- Intracellular Abeta42 accumulation is an early event in Alzheimer's disease pathogenesis.
- Preventing intraneuronal Abeta42 aggregation may offer a therapeutic strategy for AD.
- This suggests a shift in understanding AD initiation towards intracellular processes.