APP /Aβ Signaling Orchestrates Reactive Astrocyte Networks in Alzheimer's Disease
Year: 2026
Type: review
Abstract: 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.
Source: Journal of Neurochemistry
DOI: 10.1111/jnc.70526
Authors: Gretsen Velezmoro Jauregui, Sophie Coomes, Elizabeth Emmett, Alex Thatcher, Nicole Oyelakin, Maria Čarna, Jana Zelinkova, Jan Sebastian Novotny, Natalie Polakova, Tarun Kuruvilla, Robert Zorec, Alexei Verkhratsky, Vladimir Parpura, David Morgan, Kenneth L. Moya, Clara Limback‐Stokin, Gorazd Bernard Stokin
Institutions: Zhejiang Chinese Medical University, University of Bristol, Gloucestershire Health and Care NHS Foundation Trust, Imperial College London, Central European Institute of Technology – Masaryk University, Institute of Molecular and Translational Medicine, Palacký University Olomouc, University of Ljubljana, Celica (Slovenia), Sun Yat-sen University, University of Manchester, The Seventh Affiliated Hospital of Sun Yat-sen University, China Medical University, Michigan State University, Centre National de la Recherche Scientifique, Inserm, Collège de France, Université Paris Sciences et Lettres, Centre Interdisciplinaire de Recherche en Biologie, Oxford University Hospitals NHS Trust, Gloucestershire Hospitals NHS Foundation Trust
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,330
OpenAlex ID: W7170549420