Chaperone interventional therapy restores proteostasis, improves cognition and increases ADAM10 in young and aged APP knockin mice

Abstract

AbstractBackgroundTwo distinct phenotypes of Alzheimer’s disease are deficits in cognition and proteostasis, including chronic activation of the unfolded protein response (UPR) and aberrant Aβ production. The UPR is a signal transduction pathway activated in the endoplasmic reticulum (ER) at the onset of proteostatic stress. With age the UPR is less efficient and the expression of the key regulator, the chaperone BiP / Hspa5, also declines. It is unknown if restoring proteostasis by reducing chronic and aberrant UPR activation in AD can improve pathology and cognition. Here, we present data using an APP knock‐in mouse model of AD and several small molecule chaperone supplementation paradigms, including an early and late‐stage intervention.MethodTransgenic APP knock‐in mice were used as a model for AD. Two groups of mice and their wildtype littermates, (treatment starting early at 1‐2 mos old and late at 12 mos old) were administered the chemical chaperone 4‐phenyl butyrate (PBA) by weekly I.P. for 10 weeks. Controls were given I.P. injections of sterile saline. After 10 weeks of PBA or saline treatment, mice were subjected to the Spatial Object Recognition (SOR) cognitive tasks. A third group of APP knock‐in mice and wildtype littermates were given stereotaxic local hippocampal AAV‐BiP overexpression or AAV‐mCherry control injections. Following recovery and viral expression, mice were subjected to the SOR test. All mice were perfused, and tissue was collected for both immunohistochemistry and biochemical analyses.ResultPBA treatment improved performance in the SOR test both with early and late‐stage PBA interventions. AAV‐BiP overexpression recapitulated those results. Histological data indicates that chaperone treatment, both with PBA injections and AAV‐BiP overexpression, reduced hippocampal ER stress and was correlated with increased pCREB. Chronic PERK activation which leads to inhibition of protein translation was reduced, while XBP1s levels were increased with chaperone treatment. This was coupled with increased ADAM10, which is associated with non‐amyloidogenic cleavage of APPConclusionReducing proteostatic stress even at a late age improves cognition in a mouse model of Alzheimer’s disease. The implications of these results could have an impact on the development of therapies to inform the development of potential treatments for Alzheimer’s disease.