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Peer-reviewedCC BY 4.0Immunologic Research

Astrocytic endoplasmic reticulum stress as an amplifier of neuroinflammation and neurodegeneration in Alzheimer’s disease: a narrative review

  • Baraci da Silva Lima1
  • Yan Thiago Paes dos Santos1
  • Gabriel Costa Farias1
  • Elionai Felipe Rocha de Lima Souza1
  • Patrícia Danielle Lima de Lima1,2,3
  • Juarez Antônio Simões Quaresma1,2,4,5
  • Pedro Fernando da Costa Vasconcelos1,2,4,6
  • Jorge Rodrigues de Sousa1,2,4,7
7 affiliations
  1. 1School of Medicine, Universidade do Estado do Pará (UEPA), Belém, Pará Brazil
  2. 2Graduate Program in Biology of Parasitic Diseases in the Amazon (PPGBPA), Health Surveillance Secretariat, Universidade do Estado do Pará (UEPA) and Evandro Chagas Institute, Ministry of Health, Belém, Ananindeua, Pará Brazil
  3. 3Department of Morphology and Physiological Sciences, Universidade do Estado do Pará (UEPA), Belém, Pará Brazil
  4. 4Department of Pathology, Universidade do Estado do Pará (UEPA), Belém, Pará Brazil
  5. 5Department of Pathology, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, São Paulo, Brazil
  6. 6Department of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute, Health Surveillance Secretariat, Ministry of Health, Ananindeua, Pará Brazil
  7. 7Department of Clinical and Experimental Pathology, Health Surveillance Secretariat, Evandro Chagas Institute, Ministry of Health, Ananindeua, Pará Brazil
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Abstract

Alzheimer’s disease (AD) is increasingly recognized as a multicellular neuroimmune disorder in which proteostatic failure, metabolic dysfunction, and sustained glial activation interact to accelerate synaptic loss. This narrative review examines endoplasmic reticulum (ER) stress in astrocytes as a mechanistic link among the unfolded protein response (UPR), neuroinflammation, mitochondrial dysfunction, and neurodegeneration. The three canonical UPR branches, mediated by protein kinase R-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6), initially reduce protein-folding burden and reinforce ER quality control. When stress persists and adaptive capacity becomes insufficient, sustained PERK and IRE1 signaling may favor apoptosis, inflammatory transcriptional programs, cytokine production, calcium dyshomeostasis, and oxidative injury, whereas ATF6 remains predominantly associated with proteostatic reinforcement in a context-dependent manner. In astrocytes, persistent UPR activation may impair neuronal metabolic support, synaptogenic signaling, and astrocytic contributions to neurovascular homeostasis while promoting complement component 3 (C3) expression and bidirectional inflammatory crosstalk with microglia. ER-mitochondria contact sites further integrate calcium transfer, reactive oxygen species generation, bioenergetic failure, and intrinsic apoptotic signaling. Experimental evidence therefore supports a self-reinforcing neuroglial circuit in which astrocytic ER stress is proposed to function as an amplifier rather than merely a consequence of AD pathology. Therapeutic strategies targeting UPR signaling, chemical chaperones, extracellular vesicles, gene modulation, and cell-selective delivery systems remain under investigation, and their translation will require temporally controlled, cell-type-specific, and safety-conscious modulation of stress responses.

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Cite

BibTeXRIS
BibTeX
@article{lima2026astrocytic,
  title = {{Astrocytic endoplasmic reticulum stress as an amplifier of neuroinflammation and neurodegeneration in Alzheimer’s disease: a narrative review}},
  author = {Baraci da Silva Lima and Yan Thiago Paes dos Santos and Gabriel Costa Farias and Elionai Felipe Rocha de Lima Souza and Patrícia Danielle Lima de Lima and Juarez Antônio Simões Quaresma and Pedro Fernando da Costa Vasconcelos and Jorge Rodrigues de Sousa},
  journal = {Immunologic Research},
  year = {2026},
  month = nov,
  doi = {10.1007/s12026-026-09873-0},
  url = {https://doi.org/10.1007/s12026-026-09873-0},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Astrocytic endoplasmic reticulum stress as an amplifier of neuroinflammation and neurodegeneration in Alzheimer’s disease: a narrative review
AU  - Baraci da Silva Lima
AU  - Yan Thiago Paes dos Santos
AU  - Gabriel Costa Farias
AU  - Elionai Felipe Rocha de Lima Souza
AU  - Patrícia Danielle Lima de Lima
AU  - Juarez Antônio Simões Quaresma
AU  - Pedro Fernando da Costa Vasconcelos
AU  - Jorge Rodrigues de Sousa
PY  - 2026
DA  - 2026/11/05
JO  - Immunologic Research
DO  - 10.1007/s12026-026-09873-0
UR  - https://doi.org/10.1007/s12026-026-09873-0
AB  - Alzheimer’s disease (AD) is increasingly recognized as a multicellular neuroimmune disorder in which proteostatic failure, metabolic dysfunction, and sustained glial activation interact to accelerate synaptic loss. This narrative review examines endoplasmic reticulum (ER) stress in astrocytes as a mechanistic link among the unfolded protein response (UPR), neuroinflammation, mitochondrial dysfunction, and neurodegeneration. The three canonical UPR branches, mediated by protein kinase R-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6), initially reduce protein-folding burden and reinforce ER quality control. When stress persists and adaptive capacity becomes insufficient, sustained PERK and IRE1 signaling may favor apoptosis, inflammatory transcriptional programs, cytokine production, calcium dyshomeostasis, and oxidative injury, whereas ATF6 remains predominantly associated with proteostatic reinforcement in a context-dependent manner. In astrocytes, persistent UPR activation may impair neuronal metabolic support, synaptogenic signaling, and astrocytic contributions to neurovascular homeostasis while promoting complement component 3 (C3) expression and bidirectional inflammatory crosstalk with microglia. ER-mitochondria contact sites further integrate calcium transfer, reactive oxygen species generation, bioenergetic failure, and intrinsic apoptotic signaling. Experimental evidence therefore supports a self-reinforcing neuroglial circuit in which astrocytic ER stress is proposed to function as an amplifier rather than merely a consequence of AD pathology. Therapeutic strategies targeting UPR signaling, chemical chaperones, extracellular vesicles, gene modulation, and cell-selective delivery systems remain under investigation, and their translation will require temporally controlled, cell-type-specific, and safety-conscious modulation of stress responses.
SN  - 0257-277X
SN  - 1559-0755
ER  -