{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "School of Medicine, Universidade do Estado do Pará (UEPA), Belém, Pará Brazil",
    "Graduate 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",
    "Department of Morphology and Physiological Sciences, Universidade do Estado do Pará (UEPA), Belém, Pará Brazil",
    "Department of Pathology, Universidade do Estado do Pará (UEPA), Belém, Pará Brazil",
    "Department of Pathology, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, São Paulo, Brazil",
    "Department of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute, Health Surveillance Secretariat, Ministry of Health, Ananindeua, Pará Brazil",
    "Department of Clinical and Experimental Pathology, Health Surveillance Secretariat, Evandro Chagas Institute, Ministry of Health, Ananindeua, Pará Brazil"
  ],
  "article_type": "review article",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Baraci da Silva Lima",
      "orcid": "0009-0006-2777-2571"
    },
    {
      "affs": [
        0
      ],
      "name": "Yan Thiago Paes dos Santos",
      "orcid": "0009-0004-1374-9763"
    },
    {
      "affs": [
        0
      ],
      "name": "Gabriel Costa Farias",
      "orcid": "0009-0004-4769-6700"
    },
    {
      "affs": [
        0
      ],
      "name": "Elionai Felipe Rocha de Lima Souza",
      "orcid": "0009-0003-5964-4011"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Patrícia Danielle Lima de Lima",
      "orcid": "0000-0002-1068-2813"
    },
    {
      "affs": [
        0,
        1,
        3,
        4
      ],
      "name": "Juarez Antônio Simões Quaresma",
      "orcid": "0000-0002-6267-9966"
    },
    {
      "affs": [
        0,
        1,
        3,
        5
      ],
      "name": "Pedro Fernando da Costa Vasconcelos",
      "orcid": "0000-0002-6603-5527"
    },
    {
      "affs": [
        0,
        1,
        3,
        6
      ],
      "name": "Jorge Rodrigues de Sousa",
      "orcid": "0000-0003-4680-3477"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/1emmza5mdktjx.bib",
  "cited_by": 0,
  "doi": "10.1007/s12026-026-09873-0",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13740074/",
  "id": "1emmza5mdktjx",
  "issns": [
    "0257-277X",
    "1559-0755"
  ],
  "landing_url": "https://doi.org/10.1007/s12026-026-09873-0",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Review"
    ],
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      "openalex",
      "1307|Endoplasmic Reticulum Stress and Disease"
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  "openalex": "W7225307156",
  "pdf_url": "https://link.springer.com/content/pdf/10.1007/s12026-026-09873-0.pdf",
  "pmcid": "PMC13740074",
  "pmid": "42986483",
  "published": "2026-11-05",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/1emmza5mdktjx.ris",
  "sources": [
    {
      "first_seen": "2026-11-10T12:21:23Z",
      "native_id": "PMC13740074",
      "source": "pmc",
      "url": "https://doi.org/10.1007/s12026-026-09873-0"
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  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:1307|Endoplasmic Reticulum Stress and Disease",
      "subfield": "cell-biology"
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  ],
  "title": "Astrocytic endoplasmic reticulum stress as an amplifier of neuroinflammation and neurodegeneration in Alzheimer’s disease: a narrative review",
  "title_text": "Astrocytic endoplasmic reticulum stress as an amplifier of neuroinflammation and neurodegeneration in Alzheimer’s disease: a narrative review",
  "type": "peer-reviewed",
  "updated_at": "2026-11-10T12:21:23Z",
  "url": "https://research.draconitic.com/paper/1emmza5mdktjx",
  "venue": "Immunologic Research",
  "versions": []
}