APP‐mediated intracellular signaling rescues sleep impairment and blood–brain barrier leakage in Alzheimer's disease mouse model

Abstract INTRODUCTION Amyloid beta peptide (Aβ) accumulation in the brain is an Alzheimer´s disease (AD) hallmark. Sleep disturbances hamper Aβ production and clearance, thereby exacerbating the Aβ burden. The mechanisms involved remain unclear. We reported that amyloid precursor protein (APP), the Aβ source, possesses intracellular signaling that attenuates Aβ production and prevents cognitive decline in AD mice. Our follow‐up study assessed whether enhancing APP‐mediated signaling affected sleep. METHODS We expressed a membrane‐tethered APP intracellular domain (mAICD) and a variant lacking the Gα S ‐interacting site in AD mouse brains. Sleep patterns, cognitive behaviors, blood–brain barrier (BBB) integrity, and gliosis were examined. RESULTS Sleep, BBB integrity, and memory were strongly correlated. mAICD expression rescued sleep and cognitive function impairments, prevented BBB leakage, and promoted astrocyte redistribution surrounding the neurovascular units in AD mice. Gα S interaction with mAICD was critical. DISCUSSION APP‐mediated signaling plays a key role in regulating sleep, maintaining BBB integrity, and preserving memory in AD.