| First Author | Parhizkar S | Year | 2023 |
| Journal | Sci Transl Med | Volume | 15 |
| Issue | 693 | Pages | eade6285 |
| PubMed ID | 37099634 | Mgi Jnum | J:353875 |
| Mgi Id | MGI:7488332 | Doi | 10.1126/scitranslmed.ade6285 |
| Citation | Parhizkar S, et al. (2023) Sleep deprivation exacerbates microglial reactivity and Abeta deposition in a TREM2-dependent manner in mice. Sci Transl Med 15(693):eade6285 |
| abstractText | Sleep loss is associated with cognitive decline in the aging population and is a risk factor for Alzheimer's disease (AD). Considering the crucial role of immunomodulating genes such as that encoding the triggering receptor expressed on myeloid cells type 2 (TREM2) in removing pathogenic amyloid-beta (Abeta) plaques and regulating neurodegeneration in the brain, our aim was to investigate whether and how sleep loss influences microglial function in mice. We chronically sleep-deprived wild-type mice and the 5xFAD mouse model of cerebral amyloidosis, expressing either the humanized TREM2 common variant, the loss-of-function R47H AD-associated risk variant, or without TREM2 expression. Sleep deprivation not only enhanced TREM2-dependent Abeta plaque deposition compared with 5xFAD mice with normal sleeping patterns but also induced microglial reactivity that was independent of the presence of parenchymal Abeta plaques. We investigated lysosomal morphology using transmission electron microscopy and found abnormalities particularly in mice without Abeta plaques and also observed lysosomal maturation impairments in a TREM2-dependent manner in both microglia and neurons, suggesting that changes in sleep modified neuro-immune cross-talk. Unbiased transcriptome and proteome profiling provided mechanistic insights into functional pathways triggered by sleep deprivation that were unique to TREM2 and Abeta pathology and that converged on metabolic dyshomeostasis. Our findings highlight that sleep deprivation directly affects microglial reactivity, for which TREM2 is required, by altering the metabolic ability to cope with the energy demands of prolonged wakefulness, leading to further Abeta deposition, and underlines the importance of sleep modulation as a promising future therapeutic approach. |
