Atypical protein kinase C in neurodegenerative disease I: PKMzeta aggregates with limbic neurofibrillary tangles and AMPA receptors in Alzheimer disease.
Protein kinase Mzeta (PKMzeta), 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 PKMzeta in this disorder. We found that PKMzeta accumulated in neurofibrillary tangles (NFTs), whereas conventional and novel PKC isoforms did not. Unlike tau, which is present in all NFTs regardless of location, PKMzeta 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, PKMzeta 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, PKMzeta also occurred within abnormal neurites expressing MAP2, GluR1 and GluR2 as well as in perisomatic granules expressing GluR1 and GluR2, suggesting that aggregation of PKMzeta disrupts glutamatergic synaptic transmission. Together, these findings suggest a link between PKMzeta-mediated synaptic plasticity and memory impairment in AD.
Crary
John F
JF
Graduate Program in Neural and Behavioral Science, State University of New York Downstate Medical Center, Brooklyn, New York 11203, USA.
Shao
Charles Y
CY
Mirra
Suzanne S
SS
Hernandez
A Ivan
AI
Sacktor
Todd C
TC
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000096:biosynthesis; D008032:Limbic System / Q000378:metabolism* / Q000473:pathology; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D016501:Neurites / Q000378:metabolism / Q000473:pathology; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D011493:Protein Kinase C / Q000096:biosynthesis*; D018091:Receptors, AMPA / Q000378:metabolism*
D007527:Isoenzymes; D018091:Receptors, AMPA; D011493:Protein Kinase C