Atypical protein kinase C in Alzheimer's disease.

摘要

Memory impairment in Alzheimer's disease (AD) has been attributed to disruption of synaptic plasticity, but it is not known whether molecules critical for maintaining synaptic strength are directly or indirectly affected. PKMzeta, a brain-specific, autonomously active, atypical protein kinase C (aPKC) isoform, is both necessary and sufficient for maintaining enhanced alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) responses in long-term potentiation (LTP) and for memory persistence in Drosophila melanogaster. Abnormal accumulations of PKMzeta and PKCiota/lambda, a second closely related aPKC, were observed within neurofibrillary tangles (NFT), a neuropathological hallmark of AD. While PKCiota/lambda was associated with NFT throughout the brain, PKMzeta-positive NFT were found specifically in limbic regions, critical for memory formation. In contrast, the conventional and novel PKC isoforms were not identified in NFT in AD, and NFT in elderly individuals without known cognitive impairment did not accumulate PKMzeta. Additionally, cotransfection of PKMzeta and tau specifically increased phosphorylation of tau at S214 in two different cell lines, and PKMzeta colocalized with tau phosphorylated at S214 in AD brain. Tangles in transgenic mice overexpressing tau with the P301L mutation also labeled with antisera to aPKC isoforms. Dystrophic neurites in limbic regions in AD also contained aggregates of PKMzeta, colocalizing with MAP2 and accumulations of GluR1 AMPAR subunits. Sequestration of PKMzeta in tangles and neurites in the limbic system may disrupt synaptic plasticity, leading to memory loss in AD.