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Aberrant GAP-43 gene expression in Alzheimer's disease
S M de la Monte1, S C Ng, D W Hsu
1Alzheimer's Disease Research Center, Neuropathology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
The American Journal of Pathology
|October 1, 1995
Summary
Alzheimer
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Growth-associated phosphoprotein GAP-43 (Growth-Associated Protein 43) is crucial for neuronal development and synaptic plasticity.
- Aberrant neuritic growth and impaired synaptic plasticity in Alzheimer's disease (AD) suggest a role for abnormal GAP-43.
- Understanding GAP-43's role in AD may reveal novel therapeutic targets.
Purpose of the Study:
- Investigate the expression and localization of GAP-43 in Alzheimer's disease (AD) brains.
- Determine the role of GAP-43 in neurodegeneration and synaptic dysfunction in AD.
- Explore potential common mechanisms of neurodegeneration across different neurological disorders.
Main Methods:
- In situ hybridization on cerebral tissue.
- Northern blot analysis of microdissected white matter.
- Analysis of astrocytoma cell lines and primary malignant astrocytomas.
- Immunohistochemistry to assess protein localization.
Main Results:
- Reduced neuronal GAP-43 mRNA and protein expression in end-stage AD brains.
- Increased glial cell GAP-43 mRNA and protein levels in AD.
- Translocation of GAP-43 from cytosol to membranes in neuritic and glial processes in AD.
- Similar neuronal GAP-43 abnormalities observed in other neurodegenerative diseases.
Conclusions:
- Downregulated neuronal GAP-43 expression is a key molecular lesion in AD, preceding synaptic disconnection and dementia.
- Aberrantly increased glial GAP-43 expression in AD is a novel finding potentially explaining axonal loss and white matter atrophy.
- Shared neuronal abnormalities in AD and other neurodegenerative diseases suggest common underlying mechanisms.