Atypical protein kinase C in neurodegenerative disease I:: PKMδ aggregates with limbic neurofibrillary tangles and AMPA receptors in Alzheimer disease

Protein kinase M (PKM), an atypical protein kinase C (PKC) isoform, plays a key role in the maintenance of long-term potentiation (LTP), a persistent enhancement of AMPA receptor-mediated synaptic transmission, as well as in the persistence of memory in Drosophila. Because memory impairment in Alzheimer disease (AD) has been attributed to disruption of synaptic plasticity, we investigated the expression and distribution of PKM in this disorder. We found that PKMC accumulated in neurofibrillary tangles (NFTs), whereas conventional and novel PKC isoforms did not. Unlike tau, which is present in all NFTs regardless of location, PKM was found in a subset of NFTs restricted to limbic or medial temporal lobe structures (i.e. hippocampal formation, entorhinal cortex, and amygdala), areas implicated in memory loss in AD. Interestingly, PKM was not identified in any NFTs in control brains derived from 6 elderly individuals without known cognitive impairment. In medial temporal lobe structures in AD, PKM also occurred within abnormal neurites expressing MAP2, GluR1, and GluR2 as well as in perisomatic granules expressing GluR1 and GluR2, suggesting that aggregation of PKMC disrupts glutamatergic synaptic transmission. Together, these findings suggest a link between PKM xi-mediated synaptic plasticity and memory impairment in AD.