High Level Forebrain Expression of Active Tau Kinase p38y Exacerbates Cognitive Dysfunction in Aged APP-transgenic Alzheimer's Mice

improvement of cognitive deficits in Alzheimer's disease (AD), a common form of dementia, is an unattained therapeutic objective. Gene therapy holds promise for treatment of familial and sporadic forms of AD. p38y, a member of the p38 mitogen-activated protein (MAP) kinase family, inhibits amyloid-p toxicity through regulation of tau phosphorylation. We recently showed that a gene delivery approach increasing p38y resulted in markedly better learning and memory performance in mouse models of AD at advanced stages of amyloid-p- and tau-mediated cognitive impairment. Notably, low-to-moderate expression of p38y had beneficial outcomes on cognition. The impact of high levels of p38y on neuronal function remain unclear. Therefore, we addressed the outcomes of high levels of active p38y on brain function, by direct injection of p38c-encoding adenoassociated virus (AAV) into the forebrain of aged mice of an APP transgenic AD mouse model. While motor function in p38y-expressing APP transgenic mice 2 months post-injection was comparable to control treated APP mice, their activity was markedly reduced in the open field test and included frequent bouts of immobility. Moreover, their learning and memory function was markedly impaired compared to control-treated aged APP mice. These results suggest that high neuronal levels of active p38y emphasize a stress kinase role of p38y, perturbing circuit function in motivation, navigation, and spatial learning. Overall, this work shows excessive neuronal p38y levels can aggravate circuit dysfunction and advises adjustable expression systems will be required for sustainable AD gene therapy based on p38y activity. (c) 2022 IBRO. Published by Elsevier Ltd. All rights reserved.