Scavenger Receptor-A deficiency impairs immune response of microglia and astrocytes potentiating Alzheimer’s disease pathophysiology
Abstract
Late onset Alzheimer disease's (LOAD) main risk factor is aging. Although it is not well known which age-related factors are involved in its development, evidence points out to the involvement of an impaired amyloid-β (Aβ) clearance in the aged brain among possible causes. Glial cells are the main scavengers of the brain, where Scavenger Receptor class A (SR-A) emerges as a relevant player in AD because of its participation in Aβ uptake and in the modulation of glial cell inflammatory response. Here, we show that SR-A expression is reduced in the hippocampus of aged animals and APP/PS1 mice. Given that Aβ deposition increases in the aging brain, we generated a triple transgenic mouse, which accumulates Aβ and is knockout for SR-A (APP/PS1/SR-A-/-) to evaluate Aβ accumulation and the inflammatory outcome of SR-A depletion in the aged brain. The lifespan of APP/PS1/SR-A-/- mice was greatly reduced, accompanied by a 3-fold increase in plasmatic pro-inflammatory cytokines, and reduced performance in a working memory behavioral assessment. Microglia and astrocytes lacking SR-A displayed impaired oxidative response and nitric oxide production, produced up to 7-fold more pro-inflammatory cytokines and showed a 12-fold reduction in anti-inflammatory cytokines release, with conspicuous changes in lipopolysaccharide-induced glial activation. Isolated microglia from young and adult mice lacking SR-A showed a 50% reduction in phagocytic activity. Our results indicate that reduced expression of SR-A can deregulate glial inflammatory response and potentiate Aβ accumulation, two mechanisms that could contribute to AD progression.
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Loss of SR-A1 lowers microglial Aβ uptake by 60% and raises mortality and Aβ accumulation.
“SR-A1-deficiency decreases microglial Aβ uptake by 60%37,136 and increases mortality and Aβ accumulation37,136”
From Microglia in neurodegeneration (2018) · cites this paper as [136]
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Microglia in neurodegeneration
Hickman, S., Izzy, S., Sen, P., Morsett, L., & El Khoury, J. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0242-x · Cited by 1,710 · see citing works
Cai, Y., Liu, J., Wang, B., Sun, M., & Yang, H. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.856376 · Cited by 351 · see citing works
Chen, L.-L., Fan, Y.-G., Zhao, L.-X., Zhang, Q., & Wang, Z.-Y. (2023) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2022.106301 · Cited by 200 · see citing works
Guedes, J. R., Lao, T., Cardoso, A. L., & El Khoury, J. (2018) · Frontiers in Neurology · doi:10.3389/fneur.2018.00549 · Cited by 115 · see citing works
The effect of aged microglia on synaptic impairment and its relevance in neurodegenerative diseases
Triviño, J. J., & von Bernhardi, R. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.104982 · Cited by 43 · see citing works
- Authors
- Cornejo, F., Vruwink, M., Metz, C., Muñoz, P., Salgado, N., Poblete, J., Andrés, M. E., Eugenín, J., & von Bernhardi, R.
- Affiliations
- Pontificia Universidad Católica de Chile (CL)
- Universidad de Santiago de Chile (CL)
- ORCID
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2018-03
- Volume
- 69
- Pages
- 336-350
- ISSN
- 0889-1591 (ISSN-L)
- OpenAlex
- W2772306958
- Cited by
- 59
- References
- 96
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 7 · 2023: 6 · 2022: 11 · 2021: 8 · 2020: 5 · 2019: 7 · 2018: 3
- FWCI
- 2.05
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Comisión Nacional de Investigación Científica y Tecnológica
- Fondo Nacional de Desarrollo Científico y Tecnológico
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- scavenger receptor A, Alzheimer's disease, amyloid-beta clearance, microglia, astrocytes, glial inflammation, aging, inflammatory cytokines, nitric oxide, oxidative response, phagocytosis, working memory, hippocampus
- MeSH terms
- Alzheimer Disease, Animals, Astrocytes, Brain, Disease Models, Animal, Memory, Short-Term, Mice, Transgenic, Nitric Oxide, Cytokines, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Microglia, Oxidative Stress, Scavenger Receptors, Class A, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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