Sleep deprivation exacerbates microglial reactivity and Aβ deposition in a TREM2 -dependent manner in mice

Abstract

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-β (Aβ) 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 Aβ plaque deposition compared with 5xFAD mice with normal sleeping patterns but also induced microglial reactivity that was independent of the presence of parenchymal Aβ plaques. We investigated lysosomal morphology using transmission electron microscopy and found abnormalities particularly in mice without Aβ 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 Aβ 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 Aβ deposition, and underlines the importance of sleep modulation as a promising future therapeutic approach.

The effect of long-term sleep disruption on the brain – looking beyond amyloid

“…This therefore challenges the hypothesis that increased Aβ accumulation is the underlying cause of the association between sleep disruption and the increased risk for AD. This is in line with a recent study in mice where chronic sleep deprivation activated metabolic processes in the brain, independent of Aβ accumulation [24].…”

Association between hippocampal microglia, AD and LATE‐NC, and cognitive decline in older adults

“…There is substantial evidence now implicating lifestyle/psychosocial stressors 26 , 27 , 28 (eg, economic status, adverse life events, access to educational and healthcare resources, geographical factors, and others) with brain health in older adults. Additional lifestyle factors, including poor or fragmented sleep and dietary habits, 29 , 30 have also been shown to influence microglia inflammation. More recent work implicates other biological mechanisms, including dysbiosis of the gut 31 , 32 and the role of the inflammasome, innate immune sensors that regulate inflammation in response to harmful stimuli.…”

Exploring Links between Pineal Gland Calcification and Central Nervous System Disease

“…Researcher has indicated a link between reduced sleep duration and lower sleep quality in the elderly, correlating with increased Aβ deposition, further emphasizing the association between sleep disturbances and AD progression (Gao et al, 2020). Additionally, sleep disturbances have been shown to intensify microglial reactivity and promote Aβ deposition in a manner dependent on TREM-2, highlighting the intricate connection among sleep, neuroinflammation, and the pathology of AD (Parhizkar et al, 2023).…”