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Cited by 78Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

Peripheral and central neuroimmune mechanisms in Alzheimer’s disease pathogenesis

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Zhang, Shuo, Gao, Yue, Zhao, Yini, Huang, Timothy Y., Zheng, Qiuyang, Wang, Xin·2025·Molecular Neurodegeneration
DOI 10.1186/s13024-025-00812-5PMC PMC11846304
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Abstract

Alzheimer’s disease (AD) poses a growing global health challenge as populations age. Recent research highlights the crucial role of peripheral immunity in AD pathogenesis. This review explores how blood-brain barrier disruption allows peripheral immune cells to infiltrate the central nervous system (CNS), worsening neuroinflammation and disease progression. We examine recent findings on interactions between peripheral immune cells and CNS-resident microglia, forming a self-perpetuating inflammatory cycle leading to neuronal dysfunction. Moreover, this review emphasizes recent developments in the dysregulation of immune factors from both the periphery and CNS, and their impact on AD progression. With ongoing research and development of new therapeutic strategies, this review underscores the importance of modulating interactions between the peripheral immune system and CNS in AD therapy.

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Crossref · 10.1186/s13024-025-00812-5

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  • During neurodegeneration, blood-brain barrier integrity declines, which may facilitate peripheral monocytes to infiltrate the CNS and differentiate into microglia-like cells.

    “during neurodegeneration, the integrity of the blood–brain barrier declines. This may facilitate debated levels of peripheral monocytes to infiltrate the central nervous system and differentiate into microglia-like cells.”

    From Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions (2026) · cites this paper as [24]

    The Introduction (page unavailable) says that BBB compromise in Alzheimer’s disease facilitates peripheral immune-cell infiltration into the CNS. The “Other peripheral immune cells” section (page unavailable) reports monocyte-derived macrophages infiltrating the brain in late-stage AD, but does not say infiltrating monocytes differentiate into microglia-like cells; it treats peripheral monocytes and resident microglia as distinct. The claim also generalizes beyond the paper’s AD focus. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Somatic mutations present in the peripheral hematopoietic system could theoretically be imported into the brain's immune environment, posing a mechanistic link between systemic aging and local neuroinflammation.

    “any somatic mutations present in the peripheral hematopoietic system could theoretically be imported into the brain’s immune environment, posing a mechanistic link between systemic aging and local neuroinflammation [10,24,25,26].”

    From Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions (2026) · cites this paper as [24]

    The Introduction (page unavailable) says that peripheral immune cells can infiltrate the CNS and exacerbate neuroinflammation. The review does not say that somatic mutations in the peripheral hematopoietic system are carried into the brain or identify that as a mechanism linking systemic aging to local neuroinflammation; searches for somatic mutations and clonal hematopoiesis did not find such a passage. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Aging, vascular dysfunction, and chronic neuroinflammation compromise blood-brain barrier integrity, leading to increased trafficking of peripheral immune cells and microglial replacement.

    “aging, vascular dysfunction, and chronic neuroinflammation are known to compromise the integrity of the blood–brain barrier. This can lead to increased trafficking of peripheral immune cells as well as the above-mentioned microglial replacement of resident microglia by peripheral monocytes [24,36].”

    From Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions (2026) · cites this paper as [24]

    The Introduction states that compromised blood–brain barrier integrity facilitates peripheral immune-cell infiltration, and “Other peripheral immune cells” discusses replacement of resident microglia by peripheral monocytes in Alzheimer’s mouse models. The copy does not establish the claimed chain in which aging, vascular dysfunction, and chronic neuroinflammation compromise the barrier and thereby cause microglial replacement; the CD8+ T-cell section instead describes vascular dysfunction as a consequence of amyloid-associated barrier damage. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Authors
Zhang, S., Gao, Y., Zhao, Y., Huang, T. Y., Zheng, Q., & Wang, X.
Affiliations
  • Xiamen University (CN)
  • Sanford Burnham Prebys Medical Discovery Institute (US)
Corresponding author
  • Zheng, Qiuyang
  • Wang, Xin
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2025-02-21
Volume
20
Issue
1
Pages
22-22
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-025-00812-5
PMC
PMC11846304
OpenAlex
W4407842359
Cited by
78
References
147
Citations by year
2026: 56 · 2025: 22
FWCI
7.56
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • the National Key R&D Program of China (STI2030-Major-Projects-2021ZD0202400 and 2021YFA1101401)
  • the National Natural Science Foundation of China (82325018 and U21A20358 to X.W., 82271451, 82301358, 82401678)
  • Natural Science Foundation of Fujian Province of China (2021J02004)
  • Guangdong Basic and Applied Basic Research Foundation (2021B1515120081)
  • Lingang Laboratory (LG-GG-202401-ADA040102)
  • Fundamental Research Funds for the Chinese Central Universities (20720230070, 20720220052)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
Alzheimer's disease, neuroinflammation, peripheral immunity, blood-brain barrier disruption, microglia, peripheral immune cell infiltration, neuroimmune interactions, immune dysregulation, neuronal dysfunction, Alzheimer's disease treatment
MeSH terms
Neuroinflammatory Diseases, Alzheimer Disease, Animals, Blood-Brain Barrier, Central Nervous System, Humans, Neuroimmunomodulation, Microglia

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