20.500.12556/RUL-185774 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. Alzheimer's disease amyloid precursor protein amyloid‐β peptides reactive astrocytes Alzheimerjeva bolezen amiloidni prekurzorski protein amiloid-β peptidi reaktivni astrociti true false true Angleški jezik Slovenski jezik Članek v reviji 2026-08-20 09:02:53 2026-08-20 09:02:58 2026-08-21 04:30:20 0000-00-00 00:00:00 2026 0 0 19 str. iss. 7, art. e70526 Vol. 170 2026 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 616.8 1471-4159 10.1111/jnc.70526 287894275 RAZ_Velezmoro_Jauregui_Gretsen_2026.pdf RAZ_Velezmoro_Jauregui_Gretsen_2026.pdf 1 AF4DD2DAAAFA2C0997E70AC7DE203FAC c2719c223533842e5b32dcc6350ec720d2fb0f01dbc993a1b397b389d73b8278 c8b42b78-9c69-11f1-9b0d-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=244705 https://onlinelibrary.wiley.com/doi/10.1111/jnc.70526 1 cad2e956-9c64-11f1-9b0d-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=244700 Medicinska fakulteta 0 0 0