The pro‐inflammatory microRNA miR‐155 influences fibrillar β‐Amyloid1‐42 catabolism by microglia
Open accessAbstract
Microglia are the innate immune cells of the central nervous system that adopt rapid functional changes in response to Damage Associated Molecular Patterns, including aggregated β‐Amyloid (Aβ) found in Alzheimer's disease (AD). microRNAs (miRNAs) are post‐transcriptional modulators that influence the timing and magnitude of microglia inflammatory responses by downregulating the expression of inflammatory effectors. Recent studies implicate miR‐155, a miRNA known to regulate inflammatory responses, in the pathogenesis of neurodegenerative disorders including multiple sclerosis, ALS, familial Parkinson's disease, and AD. In this work, we asked if miR‐155 expression in microglia modifies cellular behaviors in response to fibrillar Aβ 1‐42 (fAβ 1‐42), in vitro. We hypothesized that in microglia, miR‐155 expression would impact the internalization and catabolism of extracellular fAβ 1‐42. Primary microglia stimulated with lipopolysaccharide demonstrate fast upregulation of miR‐155 followed by delayed upregulation of miR‐146a, an anti‐inflammatory miRNA. Conditional overexpression of miR‐155 in microglia resulted in significant upregulation of miR‐146a. Conditional deletion of miR‐155 promoted transit of fAβ 1‐42 to low‐pH compartments where catabolism occurs, while miR‐155 overexpression decreases fAβ 1‐42 catabolism. Uptake of fAβ 1‐42 across the plasma membrane increased with both up and downregulation of miR‐155 expression. Taken together, our results support the hypothesis that inflammatory signaling influences the ability of microglia to catabolize fAβ 1‐42 through interconnected mechanisms modulated by miR‐155. Understanding how miRNAs modulate the ability of microglia to catabolize fAβ 1‐42 will further elucidate the role of cellular players and molecular crosstalk in AD pathophysiology.
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Conditional expression of miR-155 in primary microglia resulted in altered catabolism of fibrillar Aβ1-42 in vitro.
“Recently, we identified a novel role for miR-155 in primary microglia, where conditional expression of miR-155 resulted in altered catabolism of fibrillar Aβ1–42 in vitro [28].”
From Microglia specific deletion of miR-155 in Alzheimer’s disease mouse models reduces amyloid-β pathology but causes hyperexcitability and seizures (2023) · cites this paper as [28]
Conditional knock-out of miR-155 in cultured neonatal microglia led to increased catabolism of fibrillar forms of Aβ1-42.
“We previously reported that conditional knock-out of miR-155 in cultured neonatal microglia led to increased catabolism of fibrillar forms of Aβ1–42 [28].”
From Microglia specific deletion of miR-155 in Alzheimer’s disease mouse models reduces amyloid-β pathology but causes hyperexcitability and seizures (2023) · cites this paper as [28]
Inducible loss of miR-155 in primary microglia in vitro increased catabolism of Aβ1-42, while overexpression of miR-155 significantly reduced catabolism.
“We observed that inducible loss of miR-155 in primary microglia in vitro resulted in increased catabolism of Aβ1–42 while overexpression of miR-155 led significantly reduced catabolism [28].”
From Microglia specific deletion of miR-155 in Alzheimer’s disease mouse models reduces amyloid-β pathology but causes hyperexcitability and seizures (2023) · cites this paper as [28]
Our work supports previous findings of a role for miR-155 in modulating catabolism of Aβ both in vitro and now in vivo.
“Our work supports previous findings of a role for miR-155 in modulating catabolism of Aβ both in vitro [28] and now, in vivo.”
From Microglia specific deletion of miR-155 in Alzheimer’s disease mouse models reduces amyloid-β pathology but causes hyperexcitability and seizures (2023) · cites this paper as [28]
Microglia functions in response to amyloid are regulated by miR-155 and contribute to circuitry vulnerability and seizures in AD pathophysiology.
“Therefore, microglia functions in response to amyloid are regulated by miR-155 (e.g., phagocytosis) [28] and contribute to circuitry vulnerability and seizures in AD pathophysiology.”
From Microglia specific deletion of miR-155 in Alzheimer’s disease mouse models reduces amyloid-β pathology but causes hyperexcitability and seizures (2023) · cites this paper as [28]
miR-155 may impair β-amyloid1-42 clearance; its knockout enhances transmembrane transport of fibrillar β-amyloid and directs it to low-pH compartments for catabolism.
“MiR-155 may impair β-amyloid1-42 clearance, as its knock-out enhances transmembrane transport of fibrillar β-amyloid and promotes directing it towards low-pH compartments for subsequent catabolism [239].”
From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [239]
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Self-citationMicroRNAs as Regulators of Phagocytosis
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- Authors
- Aloi, M. S., Prater, K. E., Sopher, B., Davidson, S., Jayadev, S., & Garden, G. A.
- Affiliations
- Baylor College of Medicine (US)
- University of Washington (US)
- Corresponding author
- Garden, Gwenn A.
- Venue
- Glia
- Publisher
- Wiley
- Published
- 2021-03-10
- Volume
- 69
- Issue
- 7
- Pages
- 1736-1748
- ISSN
- 0894-1491 (ISSN-L)
- 1098-1136
- PMC
- PMC9098129
- OpenAlex
- W3135533676
- Cited by
- 43
- References
- 9
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 14 · 2023: 13 · 2022: 8 · 2021: 2
- FWCI
- 3.70
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Glia (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute (Gilliam Fellowship for Advanced Studies)
- National Institute of General Medical Sciences (T32‐GM095421)
- National Institute on Aging (R01‐AG051437, T32‐AG052354)
- 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 › Cancer Research › MicroRNA in disease regulation
- Keywords
- miR-155, microglia, Alzheimer's disease, microRNA-146a, microglial inflammation, amyloid-beta uptake, lipopolysaccharide stimulation, neuroinflammation, amyloid-beta clearance
- MeSH terms
- Alzheimer Disease, Humans, Lipopolysaccharides, Amyloid beta-Peptides, Microglia, MicroRNAs
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