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

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 Kunitztype 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 feedforward 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.

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BibTeX RIS

BibTeX

@article{jauregui2026signaling,
  title = {{APP /Aβ Signaling Orchestrates Reactive Astrocyte Networks in Alzheimer's Disease}},
  author = {Gretsen Velezmoro Jauregui and Sophie Coomes and Elizabeth Emmett and Alex Thatcher and Nicole Oyelakin and Maria Čarna and Jana Zelinkova and Jan Sebastian Novotny and Natalie Polakova and Tarun Kuruvilla and Robert Zorec and Alexei Verkhratsky and Vladimir Parpura and David Morgan and Kenneth L Moya and Clara Limback‐stokin and Gorazd Bernard Stokin},
  journal = {Journal of Neurochemistry},
  year = {2026},
  month = oct,
  doi = {10.1111/jnc.70526},
  url = {https://hal.science/hal-05781461v1},
  note = {CC BY 4.0},
}

RIS

TY  - JOUR
TI  - APP /Aβ Signaling Orchestrates Reactive Astrocyte Networks in Alzheimer's Disease
AU  - Gretsen Velezmoro Jauregui
AU  - Sophie Coomes
AU  - Elizabeth Emmett
AU  - Alex Thatcher
AU  - Nicole Oyelakin
AU  - Maria Čarna
AU  - Jana Zelinkova
AU  - Jan Sebastian Novotny
AU  - Natalie Polakova
AU  - Tarun Kuruvilla
AU  - Robert Zorec
AU  - Alexei Verkhratsky
AU  - Vladimir Parpura
AU  - David Morgan
AU  - Kenneth L Moya
AU  - Clara Limback‐stokin
AU  - Gorazd Bernard Stokin
PY  - 2026
DA  - 2026/10/06
JO  - Journal of Neurochemistry
DO  - 10.1111/jnc.70526
UR  - https://hal.science/hal-05781461v1
AB  - 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 Kunitztype 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 feedforward 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.
SN  - 0022-3042
SN  - 1471-4159
ER  -

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