Overexpression of Aha1 and FKBP52 does not affect learning or mood‐like behavior in human tau (hTau) mice

Abstract

AbstractBackgroundTau plays a critical role in neurodegeneration, thus targeting this protein to control its accumulation is important to prevent or delay neurotoxicity in tauopathies like Alzheimer’s disease (AD). Discrete molecular chaperones, like Aha1 and FKBP52, are known to affect the stability of tau by promoting its phosphorylation, aggregation and, in some mouse models, neuronal death. However, one limitation of preclinical tau models is that various contain tau mutations which do not represent most AD cases. Our study is important because it investigates biological mechanisms and behavioral phenotype in a humanized tau (hTau) mouse model absent of tau mutations. We hypothesize that overexpression of Aha1 in in hTau mice will accelerate tau tangle formation and cognitive deficits.MethodTo test this, Tau KO and hTau mice were bilaterally injected into the hippocampus with AAV9‐Aha1, AAV9‐FKBP52, and AAV9‐mKate (control) virus. At 11 and 13 months of age, animals were tested for cognitive and behavioral phenotypes.ResultsWe found that overexpression of these chaperones does not affect anxiety, spatial working memory, and locomotion in hTau mice. We further confirmed that short‐term working memory in the learning and extinction of fear memories remained unaltered by the high levels of Aha1 and FKBP52 at these ages. Ongoing analyses will examine tau pathology in these brains by measuring tau levels, neuronal density, and cell death markers.ConclusionAt this timepoint, Aha1 and FKBP52 did not induce behavioral differences in these mice. We recently reported that overexpression of these chaperones promotes tau pathological changes in 16‐months‐old wild‐type. Thus, it is possible that behavioral differences can be detected as tau pathology progresses at an older age.