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beta-Amyloid precursor protein isoforms show correlations with neurones but not with glia of demented subjects
A W Procter1, P T Francis, C Holmes
1Miriam Marks Department of Neurochemistry, Institute of Neurology, London, UK.
Abstract:
Post-mortem cerebral cortex from 15 demented patients was specially collected to minimise autolysis and two membrane fractions and one soluble fraction were quantitatively examined for the major species of beta-amyloid precursor protein (APP) of high apparent molecular mass (> or = 80 kDa) together with the major mRNA species encoding APP isoforms. The number of pyramidal neurones and astrocytes, putative biochemical indices of interneurones and pyramidal neurones, and choline acetyl transferase activity were also determined. Multiple regression analysis has been used to investigate intercorrelations of APP species with biochemical and morphometric measures, free of any effects of confounding demographic variables. Subjects with Alzheimer's disease showed a loss of cholinergic activity and D-aspartate uptake compared with patients with other causes of dementia. The major finding of the study is that measures of neurones rather than astrocytes most closely correlate with the concentration of APP. Pyramidal cell numbers were positively correlated with mRNA for APP695. APP in the soluble fraction showed a negative correlation with pyramidal cell numbers and cholinergic activity. These results indicate that neurones within the cerebral cortex are the major source of APP, and that secretion of APP is dependent upon cortical pyramidal neuronal activity and cholinergic activity.
Insights
Neuronal activity, not glial cells, is the primary source of beta-amyloid precursor protein (APP) in the brain. Pyramidal neuron numbers correlate with APP mRNA and its secretion is linked to neuronal and cholinergic activity.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Alzheimer's disease is characterized by changes in beta-amyloid precursor protein (APP) processing and neuronal loss.
- Understanding the cellular source and regulation of APP is crucial for elucidating dementia pathogenesis.
Purpose of the Study:
- To investigate the relationship between APP species, neuronal and glial markers, and cholinergic activity in post-mortem human cerebral cortex.
- To determine the primary cellular source of APP and its regulation in dementia.
Main Methods:
- Quantitative examination of APP species and mRNA in membrane and soluble fractions from demented patients.
- Morphometric analysis of neuronal and astrocyte numbers.
- Measurement of choline acetyltransferase activity and D-aspartate uptake.
- Multiple regression analysis to correlate biochemical and morphometric measures.
Main Results:
- Neuronal measures, particularly pyramidal cell numbers, showed the strongest correlation with APP concentration, unlike astrocytes.
- Pyramidal neuron numbers positively correlated with mRNA for APP695.
- Soluble APP levels negatively correlated with pyramidal cell numbers and cholinergic activity.
- Alzheimer's disease patients exhibited reduced cholinergic activity and D-aspartate uptake compared to other dementia types.
Conclusions:
- Cortical neurons are the major source of beta-amyloid precursor protein (APP).
- APP secretion is dependent on cortical pyramidal neuronal activity and cholinergic function.
- Neuronal integrity and activity are key factors in APP metabolism in the brain.