APP/Aβ Signaling Orchestrates Reactive Astrocyte Networks in Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation, neurofibrillary pathology, synaptic dysfunction, and chronic neuroinflammation, yet the mechanisms driving early, localized pathology remain elusive. While traditionally viewed through a neuron-centric lens, astrocytes express abundant amyloid precursor protein (APP)-predominantly Kunitz-type protease inhibitor (KPI)-containing isoforms-and possess the complete enzymatic machinery for APP processing and Aβ clearance. Astrocytic APP is a stress-responsive signaling molecule regulated by inflammatory, metabolic, excitotoxic, and mechanical insults. Under local tissue stress, reactive astrocytes upregulate APP and shift toward amyloidogenic processing. The resulting bioactive fragments, including Aβ, promote astrocyte activation, disrupt homeostatic functions, and trigger feed-forward upregulation of endogenous APP. We propose that this reciprocal coupling establishes a self-reinforcing network where APP integrates local stress and diffusible Aβ propagates reactive states across the astroglial syncytium. This framework positions astrocytic APP signaling as an upstream driver of localized amyloid accumulation, neuroinflammation, and sporadic AD progression.