Haploinsufficiency of microglial MyD88 ameliorates Alzheimer's pathology and vascular disorders in APP / PS1 ‐transgenic mice
| Autor: | Tomomi Furihata, Wenqiang Quan, Wenlin Hao, Inge Tomic, Walter Schulz-Schäffer, Yang Liu, Klaus Fassbender, Michael D. Menger, Qinghua Luo |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Genetically modified mouse medicine.medical_treatment Mice Transgenic Haploinsufficiency Amyloid beta-Protein Precursor Mice 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Alzheimer Disease mental disorders Presenilin-1 medicine Animals Osteopontin Amyloid beta-Peptides Innate immune system biology Microglia Growth factor Neurodegeneration medicine.disease LRP1 Disease Models Animal 030104 developmental biology medicine.anatomical_structure nervous system Neurology Myeloid Differentiation Factor 88 biology.protein Cancer research 030217 neurology & neurosurgery |
| Zdroj: | Glia. 69:1987-2005 |
| ISSN: | 1098-1136 0894-1491 |
| DOI: | 10.1002/glia.24007 |
| Popis: | Growing evidence indicates that innate immune molecules regulate microglial activation in Alzheimer's disease (AD); however, their effects on amyloid pathology and neurodegeneration remain inconclusive. Here, we conditionally deleted one allele of myd88 gene specifically in microglia in APP/PS1-transgenic mice by 6 months and analyzed AD-associated pathologies by 9 months. We observed that heterozygous deletion of myd88 gene in microglia decreased cerebral amyloid β (Aβ) load and improved cognitive function of AD mice, which was correlated with reduced number of microglia in the brain and inhibited transcription of inflammatory genes, for example, tnf-α and il-1β, in both brain tissues and individual microglia. To investigate mechanisms underlying the pathological improvement, we observed that haploinsufficiency of MyD88 increased microglial recruitment toward Aβ deposits, which might facilitate Aβ clearance. Microglia with haploinsufficient expression of MyD88 also increased vasculature in the brain of APP/PS1-transgenic mice, which was associated with up-regulated transcription of osteopontin and insulin-like growth factor genes in microglia. Moreover, MyD88-haploinsufficient microglia elevated protein levels of LRP1 in cerebral capillaries of APP/PS1-transgenic mice. Cell culture experiments further showed that treatments with interleukin-1β decreased LRP1 expression in pericytes. In summary, haploinsufficiency of MyD88 in microglia at a late disease stage attenuates pro-inflammatory activation and amyloid pathology, prevents the impairment of microvasculature and perhaps also protects LRP1-mediated Aβ clearance in the brain of APP/PS1-transgenic mice, all of which improves neuronal function of AD mice. |
| Databáze: | OpenAIRE |
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