Overexpression of protein kinase Mζ in the hippocampal dentate gyrus rescues amyloid-β-induced synaptic dysfunction within entorhinal-hippocampal circuit

Entorhinal cortex (EC) is one of the first cerebral regions affected in the early phase of Alzheimer's disease (AD). Soluble forms of amyloid beta (A beta) impair synaptic transmission in experimental AD models. Protein kinase M zeta (PKM zeta) is an atypical persistently active protein kinase C, known to maintain long term synaptic plasticity and memory, but its role in AD has not yet been described. We examined effect of PKM zeta overexpression on the late long-term potentiation (L-LTP) in the dentate gyrus (DG) following EC amyloidopathy. Oligomeric A beta 1-42 (oA beta) or vehicle was bilaterally microinjected into the EC of the male Wistar rats. After 1 week, 2 mu L of lentiviral vector (similar to 10(8) TU/mL) encoding PKM zeta - genome was injected into the DG. One week later, synaptic responses and the LTP persistence were assessed in DG of freely moving animals during 90 minutes to 7 days period. Novel object recognition, passive avoidance and spatial memories were also tested. In rats with EC amyloidopathy, LTP was induced with less amplitude compared to the control group, and extinguished after 24 h. PKM zeta - overexpression in DG augmented synaptic responses (PS-LTP amplitudes) and maintained LTP over 1 week. PKM zeta ameliorated recognition and memory deficits in rats with EC amyloidopathy. Microinjection of PKM zeta inhibitor, zeta inhibitory peptide, into the DG abolished the boosting effect of PKM zeta on synaptic activity and memory performance. PKM zeta dependent pathway could be a potential therapeutic target to combat synaptic failure and memory deficit in the early phase of AD. (C) 2021 Elsevier Inc. All rights reserved.

Automated summary

EC amyloidopathy leads to impaired synaptic transmission and memory deficits, while overexpression of PKM zeta in DG enhances synaptic responses and improves memory performance, suggesting PKM zeta may serve as a potential therapeutic target for early stage AD.