Phosphorylation of MARCKS in Alzheimer disease brains

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Abstract
Activation of the amyloid β-protein precursor, secretary pathway through α-secretase has been reported to increase the secretion of neuroprotective amyloid precursor protein and preclude the formation of amyloid β-protein. Activation of protein kinase C has been shown to accelerate this secretory pathway. These results prompted us to focus on a potential links between protein kinase C and the amyloid β-protein-related pathology of Alzheimer disease (AD). Although protein kinase C is reported to occur in senile plaques, its catalytic activity has not been investigated. As the phosphorylation of myristoylated alanine-rich C kinase substrate (MARCKS) has been used as a marker for activation of protein kinase C in vivo, we examined its phosphorylation in brain tissues obtained from seven AD patients and five non-demented subjects using an antibody that specifically recognized MARCKS phosphorylated by protein kinase C. Phosphorylation of MARCKS in cortical neurons in AD brains was weaker than that in control brains. Interestingly, however, phosphorylation of MARCKS was detected in microglia and dystrophic neurites within neuritic plaques, a mature form of amyloid β-protein deposits. These results suggest that protein kinase C alteration is associated with AD pathology and that protein kinase C is activated in microglia and dystrophic neurites by amyloid β-protein in AD brains.