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The neurotoxicity of amyloid beta protein in aged primates
A C McKee1, N W Kowall, J S Schumacher
1Geriatric Research Educational and Clinical Center, Bedford Veterans Administration Medical Center, MA 01730, USA.
Abstract:
Amyloid beta protein deposition is a universal feature of Alzheimer's disease brain. To investigate the effects of amyloid beta protein in aged primates, intracerebral microinjections of solubilized amyloid beta (A beta (1-40)) and control peptides were made into the frontal cortex of 7 primates under stereotactic guidance. Control injections consisted of vehicle alone, a 37 amino acid non toxic peptide (A37), scrambled peptide (CA4), and reverse peptide (A beta (40-1)). Amyloid beta peptide produced dose-dependent cortical lesions that were significantly larger than those produced by vehicle or by isomolar control peptides (3.28 and 2.20 fold larger respectively) (p = < 0.005). In 5 aged primates, the cortex surrounding the amyloid beta lesions contained argyrophilic, thioflavine S fluorescent, Alz 50 and ubiquitin immunoreactive neurons and perikarya. The number of Alz 50 immunoreactive neurons surrounding the amyloid beta injections was significantly greater (mean 127 +/- 39) than the number found surrounding reverse peptide injections (mean 20 +/- 13) and other control peptides (mean 0.8 +/- 0.3) (p < 0.05). Neuronal and neuritic alterations were not found adjacent to the amyloid beta peptide lesions in young monkeys and control injections produced insignificant Alz 50 neuronal positivity. These findings suggest that amyloid beta peptide is neurotoxic in primate brain and that the cytoskeletal response to amyloid beta protein is specific and age-related.
Insights
Amyloid beta protein causes brain lesions in primates, with effects varying by age. This neurotoxicity and age-related cytoskeletal response are key findings for Alzheimer's disease research.
Area of Science:
- Neuroscience
- Pathology
- Primate Models
Background:
- Amyloid beta protein deposition is characteristic of Alzheimer's disease.
- Understanding amyloid beta's neurotoxic effects in primates is crucial for disease modeling.
Purpose of the Study:
- To investigate the neurotoxic effects of amyloid beta protein (A beta (1-40)) in aged primates.
- To examine the age-related cytoskeletal response to amyloid beta protein.
Main Methods:
- Stereotactic microinjections of amyloid beta (A beta (1-40)) and control peptides into the frontal cortex of aged primates.
- Analysis of cortical lesions and neuronal/neuritic alterations using histological and immunohistochemical markers (argyrophilia, thioflavine S, Alz 50, ubiquitin).
Main Results:
- Amyloid beta peptide induced dose-dependent cortical lesions significantly larger than controls.
- Aged primates showed specific cytoskeletal responses (Alz 50 positivity) around amyloid beta lesions.
- Neuronal and neuritic alterations were age-dependent, not observed in young monkeys or with control peptides.
Conclusions:
- Amyloid beta peptide is neurotoxic in the primate brain.
- The cytoskeletal response to amyloid beta protein is specific and age-related, offering insights into Alzheimer's pathogenesis.