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

Amini, N ; Sharif University of Technology | 2021

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  1. Type of Document: Article
  2. DOI: 10.1016/j.brainresbull.2020.11.001
  3. Publisher: Elsevier Inc , 2021
  4. Abstract:
  5. Accumulation of amyloid beta (Aβ) soluble forms in the cerebral parenchyma is the mainstream concept underlying memory deficit in the early phase of Alzheimer's disease (AD). PKMζ 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 PKMζ overexpression on AD-related memory impairment in rats. Oligomeric form of Aβ (oAβ) or vehicle was bilaterally microinjected into the dorsal hippocampus of male Wistar rats under stereotaxic surgery. One week later, 2 μl of lentiviral vector (108 T.U. / ml.) encoding PKMζ 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 oAβ impairs both passive avoidance and spatial learning and memory. However, overexpression of PKMζ in the dorsal hippocampus restored the behavioral performance. This improving effect was blocked by microinjection of ZIP, a PKMζ inhibitor, into the hippocampus. oAβ or PKMζ did not significantly change GluA1 level in the hippocampus. Furthermore, PKMζ failed to restore elevated KCC2 level induced by oAβ. However, oAβ decreased GluA2 level, and overexpression of PKMζ restored its expression toward the control level. In conclusion, hippocampal overexpression of PKMζ restored memory dysfunction induced by amyloidopathy in part, through preserving hippocampal GluA2 containing AMPA receptors. PKMζ’s signaling pathway could be considered as a therapeutic target to battle memory deficits in the early phase of AD. © 2020 Elsevier Inc
  6. Keywords:
  7. AMPA receptor ; Amyloid beta protein ; Glutamate receptor 1 ; Glutamate receptor 2 ; Potassium chloride cotransporter 2 ; Protein kinase C zeta ; Adult ; Alzheimer disease ; Animal experiment ; Animal model ; Brain function ; Cognitive defect ; Controlled study ; Dorsal hippocampus ; Gene overexpression ; Glutamatergic synapse ; Histopathology ; Male ; Morris water maze test ; Nonhuman ; Oligomerization ; Passive avoidance ; Priority journal ; Protein expression ; Rat ; Signal transduction ; Spatial learning ; Spatial memory ; Stereotaxic surgery ; Western blotting
  8. Source: Brain Research Bulletin ; Volume 166 , 2021 , Pages 64-72 ; 03619230 (ISSN)
  9. URL: https://www.sciencedirect.com/science/article/abs/pii/S0361923020306791