Overexpression of protein kinase Mζ in the hippocampus mitigates Alzheimer's disease-related cognitive deficit in rats

Accumulation of amyloid beta (A beta) soluble forms in the cerebral parenchyma is the mainstream concept underlying memory deficit in the early phase of Alzheimer's disease (AD). PKM zeta plays a critical role in the maintenance of long-term memory. Yet, the role of this brain-specific enzyme has not been addressed in AD. We examined the impact of hippocampal PKM zeta overexpression on AD-related memory impairment in rats. Oligomeric form of A beta (oA beta) or vehicle was bilaterally microinjected into the dorsal hippocampus of male Wistar rats under stereotaxic surgery. One week later, 2 mu l of lentiviral vector (10(8) T.U./ml.) encoding PKM zeta genome was microinjected into the dorsal hippocampus. Seven days later, behavioral performance was assessed using shuttle box and Morris water maze. The expression levels of GluA1, GluA2 and KCC2 were determined in the hippocampus using western blot technique. Our data showed that oA beta impairs both passive avoidance and spatial learning and memory. However, overexpression of PKM zeta in the dorsal hippocampus restored the behavioral performance. This improving effect was blocked by micminjection of ZIP, a PKM zeta inhibitor, into the hippocampus. oA beta or PKM zeta did not significantly change GluA1 level in the hippocampus. Furthermore, PKM zeta failed to restore elevated KCC2 level induced by oAp. However, oA beta decreased GluA2 level, and overexpression of PKM zeta restored its expression toward the control level. In conclusion, hippocampal overexpression of PKM zeta restored memory dysfunction induced by amyloidopathy in part, through preserving hippocampal GluA2 containing AMPA receptors. PKM zeta's signaling pathway could be considered as a therapeutic target to battle memory deficits in the early phase of AD.

Automated summary

The overexpression of hippocampal PKM zeta can restore memory dysfunction induced by amyloidopathy in the early phase of AD, partly through preserving GluA2-containing AMPA receptors in the hippocampus. This suggests that PKM zeta's signaling pathway could be a potential therapeutic target for combating memory deficits in AD.