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

## TL;DR

A protein fragment called mAICD improves sleep, brain barrier function, and memory in a mouse model of Alzheimer's disease.

## Contribution

APP-mediated signaling, specifically mAICD and its interaction with GαS, is shown to rescue sleep and BBB integrity in AD mice.

## Key findings

- mAICD expression rescues sleep and cognitive impairments in AD mice.
- mAICD prevents blood–brain barrier leakage and promotes astrocyte redistribution.
- GαS interaction with mAICD is critical for preserving BBB, sleep, and cognition.

## Abstract

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.

We expressed a membrane‐tethered APP intracellular domain (mAICD) and a variant lacking the GαS‐interacting site in AD mouse brains. Sleep patterns, cognitive behaviors, blood–brain barrier (BBB) integrity, and gliosis were examined.

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. GαS interaction with mAICD was critical.

APP‐mediated signaling plays a key role in regulating sleep, maintaining BBB integrity, and preserving memory in AD.

Sleep, cognition, and BBB permeability are tightly interconnected.mAICD brain expression restores sleep and prevents vascular impairments in AD mice.mAICD interaction with GαS is necessary to preserve BBB, sleep, and cognition.mAICD redistributes astrocytes in NVUs through GαS signaling.

Sleep, cognition, and BBB permeability are tightly interconnected.

mAICD brain expression restores sleep and prevents vascular impairments in AD mice.

mAICD interaction with GαS is necessary to preserve BBB, sleep, and cognition.

mAICD redistributes astrocytes in NVUs through GαS signaling.