Genetic and Pharmacological Targeting of Hsp72 Overexpression/Induction in an Alzheimer's Disease Mouse Model With Combined Amyloid and Tau Pathology.

Abstract

Heat shock protein 72 (Hsp72), a stress-inducible member of the Hsp70 family, has been implicated in mitigating the pathogenic effects of amyloid-beta (Aβ) and tau pathology; both key factors associated with the development and progression of Alzheimer's disease (AD). However, no in vivo study has been conducted to investigate the ability of Hsp72 to provide benefit when both Aβ and tau pathology are present concurrently. This study set out to utilize a genetic approach (transgenic overexpression) and a pharmacological validation approach (BGP-15) to increase Hsp72 expression in mice exhibiting Aβ and tau pathology (5xFADxTg30 model). Our findings indicate that genetic Hsp72 overexpression did not significantly alter Aβ or tau burden, deficits in motor performance, or alterations to body composition in this model, but modestly improved survival rates (driven by findings in male mice) and altered anxiety-like behavior (driven by findings in female mice). Similarly, BGP-15 treatment was unable to rescue behavioral traits, motor deficits, body composition, or alleviate Aβ or tau accumulation, although this treatment also showed a trend towards enhancing survival (again in male mice) and altered anxiety-like behavior (specifically in female mice). While the 5xFADxTg30 mice demonstrated seizure susceptibility compared to WT mice, BGP-15 was unable to alleviate this trait. These findings were independent of any measurable increase in Hsp72 abundance in the brain in response to BGP-15. Together, these findings suggest a limited impact of genetic overexpression and pharmacological targeting of Hsp72 protein abundance in this combined Aβ and tau model, although some sex-specific differences are noted.