MyD88 Deficiency Ameliorates β-Amyloidosis in an Animal Model of Alzheimer's Disease
Open accessAbstract
The accumulation of β-amyloid protein (Aβ) in the brain is thought to be a primary etiologic event in Alzheimer's disease (AD). Fibrillar Aβ plaques, a hallmark of AD abnormality, are closely associated with activated microglia. Activated microglia have contradictory roles in the pathogenesis of AD, being either neuroprotective (by clearing harmful Aβ and repairing damaged tissues) or neurotoxic (by producing proinflammatory cytokines and reactive oxygen species). Aβ aggregates can activate microglia by interacting with multiple toll-like receptors (TLRs), the pattern-recognition receptors of the innate immune system. Because the adapter protein MyD88 is essential for the downstream signaling of all TLRs, except TLR3, we investigated the effects of MyD88 deficiency (MyD88(-/-)) on Aβ accumulation and microglial activation in an AD mouse model. MyD88 deficiency decreased Aβ load and microglial activation in the brain. The decrease in Aβ load in an MyD88(-/-) AD mouse model was associated with increased and decreased protein expression of apolipoprotein E (apoE) and CX3CR1, respectively, compared with that in an MyD88 wild-type AD mouse model. These results suggest that MyD88 deficiency may reduce Aβ load by enhancing the phagocytic capability of microglia through fractalkine (the ligand of CX3CR1) signaling and by promoting apoE-mediated clearance of Aβ from the brain. These findings also suggest that chronic inflammatory responses induced by Aβ accumulation via the MyD88-dependent signaling pathway exacerbate β-amyloidosis in AD.
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Targeting MyD88 has yielded contradictory effects in AD models possibly due to differential effects on XO4+ and XO4− populations.
“targeting MyD88 has also yielded contradictory effects in AD models72,73 possibly due to differential effects on XO4+ and XO4− populations.”
From Transcriptional signature in microglia associated with Aβ plaque phagocytosis (2021) · cites this paper as [72]
The Discussion (page not provided) reports that MyD88 deficiency reduced amyloid load and contrasts this with differing effects of targeting individual TLRs in AD mouse models. It does not report contradictory effects of targeting MyD88 itself or attribute any differences to XO4+ and XO4− populations. (LLM, conf=0.82)
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- Authors
- Lim, J.-E., Kou, J., Song, M., Pattanayak, A., Jin, J., Lalonde, R., & Fukuchi, K.-I.
- Affiliations
- Peoria campus of the University of Illinois System (US)
- Université de Rouen Normandie (FR)
- Corresponding author
- Fukuchi, Ken-ichiro
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2011-09
- Volume
- 179
- Issue
- 3
- Pages
- 1095-1103
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC3157279
- OpenAlex
- W2123288685
- Cited by
- 63
- References
- 10
- Citations by year
- 2026: 3 · 2024: 2 · 2023: 6 · 2022: 4 · 2021: 4 · 2020: 1 · 2019: 4 · 2018: 3 · 2017: 3 · 2016: 2 · 2015: 9 · 2014: 7 · 2013: 5 · 2012: 8
- FWCI
- 3.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AG030399, EY018478, AG029818, AG031979)
- Alzheimer's Association (IIRG-07-59494)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- MyD88, beta-amyloidosis, Alzheimer's disease, microglial activation, Toll-like receptors, innate immunity, apolipoprotein E, CX3CR1, fractalkine, phagocytosis, neuroinflammation, amyloid plaque clearance
- MeSH terms
- CX3C Chemokine Receptor 1, Alzheimer Disease, Animals, Apolipoproteins E, Enzyme-Linked Immunosorbent Assay, Female, Male, Mice, Inbred C57BL, Amyloid beta-Peptides, Cerebral Amyloid Angiopathy, Microglia, Receptors, Chemokine, Mice, Myeloid Differentiation Factor 88, Cerebrum
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