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While traditionally viewed through a neuron\u2010centric lens, astrocytes express abundant amyloid precursor protein (APP)\u2014predominantly Kunitz\u2010type protease inhibitor (KPI)\u2010containing isoforms\u2014and possess the complete enzymatic machinery for APP processing and A\u03b2 clearance. Astrocytic APP is a stress\u2010responsive 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 A\u03b2, promote astrocyte activation, disrupt homeostatic functions, and trigger feed\u2010forward upregulation of endogenous APP. We propose that this reciprocal coupling establishes a self\u2010reinforcing network where APP integrates local stress and diffusible A\u03b2 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.<\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70526-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70526","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T12:03:46Z","timestamp":1784894626000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>APP<\/scp>\n                    \/A\u03b2 Signaling 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