Cited by 49Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

Microglia in Alzheimer's Disease: a Key Player in the Transition Between Homeostasis and Pathogenesis

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McFarland, Karen N., Chakrabarty, Paramita·2022·Neurotherapeutics

Abstract

Immune activation accompanies the development of proteinopathy in the brains of Alzheimer's dementia patients. Evolving from the long-held viewpoint that immune activation triggers the pathological trajectory in Alzheimer's disease, there is accumulating evidence now that microglial activation is neither pro-amyloidogenic nor just a simple reactive process to the proteinopathy. Preclinical studies highlight an interesting aspect of immunity, i.e., spurring immune system activity may be beneficial under certain circumstances. Indeed, a dynamic evolving relationship between different activation states of the immune system and its neuronal neighbors is thought to regulate overall brain organ health in both healthy aging and progression of Alzheimer's dementia. A new premise evolving from genome, transcriptome, and proteome data is that there might be at least two major phases of immune activation that accompany the pathological trajectory in Alzheimer's disease. Though activation on a chronic scale will certainly lead to neurodegeneration, this emerging knowledge of a potential beneficial aspect of immune activation allows us to form holistic insights into when, where, and how much immune system activity would need to be tuned to impact the Alzheimer's neurodegenerative cascade. Even with the trove of recently emerging -omics data from patients and preclinical models, how microglial phenotypes are functionally related to the transition of a healthy aging brain towards progressive degenerative state remains unknown. A deeper understanding of the synergism between microglial functional states and brain organ health could help us discover newer interventions and therapies that enable us to address the current paucity of disease-modifying therapies in Alzheimer's disease.

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  • Alzheimer's neuroinflammation is a dynamic balance between protective and harmful microglial programs, with disease stage and local tissue environment determining whether immune activation is beneficial, insufficient, maladaptive, or toxic.

    “Reviews and experimental studies now increasingly describe Alzheimer’s neuroinflammation as a dynamic balance between protective and harmful microglial programs, with disease stage and local tissue environment determining whether immune activation is beneficial, insufficient, maladaptive, or toxic [13,19].”

    From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [13]

    The Introduction describes early microglial activation as potentially protective and later chronic inflammation as potentially harmful; the section on preclinical models also describes context-dependent changes. But that section says whether specific microglial profiles relate to disease staging is unknown, so the claim that stage determines the outcome is stronger than the review supports. The four-way classification, particularly ‘insufficient’ activation, is not established in these passages. Page numbers were not available in our copy. (LLM, conf=0.84)

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  • Microglia may help contain amyloid plaques, phagocytose pathological material, support synapses, and limit inflammatory spread; yet they may also release pro-inflammatory mediators, promote complement-associated synapse loss, propagate neurotoxic signaling, and contribute to chronic tissue damage.

    “Microglia may help contain amyloid plaques, phagocytose pathological material, support synapses, and limit inflammatory spread; yet they may also release pro-inflammatory mediators, promote complement-associated synapse loss, propagate neurotoxic signaling, and contribute to chronic tissue damage.”

    From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [13]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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  • Microglial responses in Alzheimer's disease are not uniformly harmful and cannot be reduced to a simple activated-versus-resting distinction.

    “more recent work suggests that microglial responses in Alzheimer’s disease are not uniformly harmful and cannot be reduced to a simple activated-versus-resting distinction [13,14].”
  • The same broad category of microglial activation can describe processes with opposite biological consequences.

    “The central unresolved issue is that the same broad category of “microglial activation” can describe processes with opposite biological consequences.”

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Authors
McFarland, K. N., & Chakrabarty, P.
Affiliations
University of Florida (US)
Corresponding author
Chakrabarty, Paramita
Venue
Neurotherapeutics
Publisher
Elsevier BV
Published
2022-01
Volume
19
Issue
1
Pages
186-208
ISSN
1878-7479 (ISSN-L)
OpenAlex
W4221004276
Cited by
48
References
265
Citations by year
2026: 8 · 2025: 8 · 2024: 15 · 2023: 10 · 2022: 7
FWCI
1.03
Type
journal article
Language
en
Open access
Locations
  • Neurotherapeutics (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
national institutes of health (P30AG066506, RF1AG064914)
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
microglia, Alzheimer's disease, microglial activation, neuroinflammation, amyloid-beta, neurodegeneration, healthy aging, microglial phenotype, disease-modifying therapy
MeSH terms
Alzheimer Disease, Brain, Homeostasis, Humans, Neurons, Microglia

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