In Tired Mice, TREM2 Addles Microglia
As anyone who’s tossed and turned through sleepless nights will know, chronic sleep deprivation can turn the simplest task into a challenge. Microglia, it turns out, suffer similarly from no shuteye. According to a study published April 26 in Science Translational Medicine, in mice chronically deprived of sleep, microglia shift from homeostatic sentinels into reactive, yet ineffectual, responders to threats.
- In sleep-deprived mice, microglia slipped into an activated state marked by endolysosomal dysfunction.
- Most of this transition depended on TREM2 signaling.
- These microglia internalized Aβ fibrils but failed to fully digest them.
Even without Aβ plaques around, in tired mice the cells partially transitioned into a disease-associated state and accumulated distended lysosomes with a dearth of digestive enzymes. When amyloid-ridden mice were kept awake, their immune cells did encircle Aβ plaques, only to choke on Aβ fibrils that they failed to digest.
TREM2 signaling was responsible for inciting much of this zombie-like state. Curiously, though, even in mice lacking the functional receptor, loss of sleep still took a toll, provoking metabolic disturbances within microglia that likely hindered their function. David Holtzman of Washington University in St. Louis oversaw the study.
The effects of poor sleep played out differently at the transcriptional and functional level depending on the presence of intact TREM2 and/or Aβ plaques. To first author Samira Parhizkar, the take-home message from this nuanced study is clear: “One way or another, sleep deprivation is bad.”
“This study is truly remarkable,” commented Joana Pereira of the Karolinska Institute in Stockholm. “There was already evidence from other research groups that sleep loss is associated with greater amyloid pathology. However, their study indicates that, independently of the vulnerability to develop amyloid plaques, sleep impairs TREM2-dependent microglial functions, which can increase not only the risk to develop Alzheimer’s disease but also many other disorders.”
To Tharick Pascoal of University of Pittsburgh, the study reflects a field that is evolving from the dual concept of microglial activation versus inactivation to recognizing nuanced phenotypes marked by varying levels of different proteins such as TREM2. “This paper adds another layer of complexity to this model by suggesting that external factors such as chronic sleep deprivation may modulate the effects of these proteins in determining disease-related microglial phenotypes,” he said.
Sleep and Alzheimer’s disease are intertwined. Numerous studies have tied poor sleep with elevated AD biomarkers (Jan 2018 news; Apr 2018 news; Jan 2019 news). Astrocytes play a role in regulating the brain’s circadian clock, and microglia and other cells in the brain modulate their activity in step with this rhythm (Dec 2018 conference news). Exactly how microglia respond to sleep loss is unclear, though inflammation rises in response to chronic sleep loss (Mullington et al., 2010; Wright et al., 2015; Irwin et al., 2016).
By design, microglia are supremely responsive to subtle changes in their environment. How might lack of sleep influence them? To investigate, the researchers used mice expressing the common variant of human TREM2, the hypofunctional R47H variant, or no TREM2 at all. Starting at 10 weeks old, the mice were moved to a sleep fragmentation chamber, where a swipe bar swiped across their cages every 30 seconds during a six-hour stint each day, keeping the nocturnal rodents awake when they would normally sleep.
After six weeks of this, microglia expressing the common variant of TREM2 were profoundly changed. Even without Aβ plaques in the picture—stay tuned for that—microglia were in a partial DAM-like state, expressing some of the genes that typically ramp up in mouse models of amyloidosis. The cells were loaded with distended lysosomes containing abnormally few digestive enzymes, as well as autophagosomes and lysosomes that appeared suspended in the act of fusion. This endolysosomal congestion rendered the cells incapable of digesting fluorescently labeled Aβ fibrils that the researchers injected into the mice's brains. Notably, TREM2 signaling orchestrated most of these particular responses to fragmented sleep, as they were not observed to the same extent in TREM2-deficient mice.
Strung Out. Transmission electron micrographs of microglial lysosomes revealed a dramatic increase in size as well as number of electron-dense inclusions within them in sleep-deprived mice (right) compared to control (left). [Courtesy of Parhizkar et al., Science Translational Medicine, 2023.]
Neurons and astrocytes also displayed an abundance of ballooning lysosomes. Oddly, these effects also depended on TREM2. “These data suggest that in the absence of Aβ plaques, sleep deprivation acts as a primary metabolic stressor impairing microglial lysosomal functions, which may also result in additional burden on neurons that are unable to process and excrete substrates,” the authors wrote.
How might microglia that are dealing with amyloid plaques respond to forced wakefulness? To find out, the scientists inflicted the six-week sleep loss on 5xFAD mice at 10 weeks of age, just as plaques were appearing. Compared to their slumbering counterparts, sleepless 5xFAD mice had double the Aβ plaque burden—even though their microglia encircled plaques more frantically than those in normal sleepers. Alas, while they rallied to the scene, the tired microglia failed to seal the deal. They engulfed Aβ fibrils but could not digest them.
In 5xFAD mice lacking functional TREM2, sleep loss barely affected plaque load, nor did it incite microglia to surround plaques. This might be because TREM2-deficient mice already had more plaques prior to sleep deprivation, and TREM2 is required for microglial recruitment to plaques.
Oddly, many of the responses to sleep loss observed in mice without amyloid did not happen in plaque-ridden mice. For example, sleep deprivation did not lead to a glut of distended lysosomes in 5xFAD microglia. The authors believe this suggests that how microglia react to sleep deprivation depends on their baseline reactivity, which is determined by a combination of their genotype and past exposures.
The paper contains detailed comparisons of transcriptomic and CSF proteomic responses to sleep loss in mice of all genotypes. The upshot? Sleep loss affected microglia differently depending on their genotype and exposure to plaques, but regardless of their situation, microglia suffer metabolic and endolysosomal malfunctions in mice that don't sleep.
Detailed human studies of microglial responses to sleep deprivation have not been done. One study found that in people with poor self-reported sleep, levels of soluble sTREM2, a marker of microglial activation, are higher in CSF (Hu et al., 2021).
Another recent study, also from WashU scientists, reported that a single treatment with suvorexant, a dual orexin receptor agonist prescribed to treat insomnia, lowered CSF markers of phospho-tau in cognitively normal people. That study did not report if suvorexant affected sTREM2 or other microglial markers (Lucey et al., 2023).—Jessica Shugart
- Skimping on Sleep Makes For More Aβ in the Brain
- Does Amyloid Accumulate After a Single Sleepless Night?
- Tau, More than Aβ, Affects Sleep Early in Alzheimer’s
- When Glial Clocks Fall Out of Sync, Inflammation Ensues
- Mullington JM, Simpson NS, Meier-Ewert HK, Haack M. Sleep loss and inflammation. Best Pract Res Clin Endocrinol Metab. 2010 Oct;24(5):775-84. PubMed.
- Wright KP Jr, Drake AL, Frey DJ, Fleshner M, Desouza CA, Gronfier C, Czeisler CA. Influence of sleep deprivation and circadian misalignment on cortisol, inflammatory markers, and cytokine balance. Brain Behav Immun. 2015 Jul;47:24-34. Epub 2015 Jan 29 PubMed.
- Irwin MR, Olmstead R, Carroll JE. Sleep Disturbance, Sleep Duration, and Inflammation: A Systematic Review and Meta-Analysis of Cohort Studies and Experimental Sleep Deprivation. Biol Psychiatry. 2016 Jul 1;80(1):40-52. Epub 2015 Jun 1 PubMed.
- Hu HY, Ma LZ, Hu H, Bi YL, Ma YH, Shen XN, Ou YN, Dong Q, Tan L, Yu JT. Associations of Sleep Characteristics with Cerebrospinal Fluid sTREM2 in Cognitively Normal Older Adults: the CABLE Study. Neurotox Res. 2021 Aug;39(4):1372-1380. Epub 2021 Jun 7 PubMed.
- Lucey BP, Liu H, Toedebusch CD, Freund D, Redrick T, Chahin SL, Mawuenyega KG, Bollinger JG, Ovod V, Barthélemy NR, Bateman RJ. Suvorexant Acutely Decreases Tau Phosphorylation and Aβ in the Human CNS. Ann Neurol. 2023 Mar 10; PubMed.
- Sharma RA, Varga AW, Bubu OM, Pirraglia E, Kam K, Parekh A, Wohlleber M, Miller MD, Andrade A, Lewis C, Tweardy S, Buj M, Yau PL, Sadda R, Mosconi L, Li Y, Butler T, Glodzik L, Fieremans E, Babb JS, Blennow K, Zetterberg H, Lu SE, Badia SG, Romero S, Rosenzweig I, Gosselin N, Jean-Louis G, Rapoport DM, de Leon MJ, Ayappa I, Osorio RS. Obstructive Sleep Apnea Severity Affects Amyloid Burden in Cognitively Normal Elderly. A Longitudinal Study. Am J Respir Crit Care Med. 2018 Apr 1;197(7):933-943. PubMed.
- Parhizkar S, Gent G, Chen Y, Rensing N, Gratuze M, Strout G, Sviben S, Tycksen E, Zhang Q, Gilmore PE, Sprung R, Malone J, Chen W, Remolina Serrano J, Bao X, Lee C, Wang C, Landsness E, Fitzpatrick J, Wong M, Townsend R, Colonna M, Schmidt RE, Holtzman DM. Sleep deprivation exacerbates microglial reactivity and Aβ deposition in a TREM2-dependent manner in mice. Sci Transl Med. 2023 Apr 26;15(693):eade6285. PubMed.
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This study is truly remarkable. There was already evidence from other research groups that sleep loss is associated with greater amyloid pathology. However, their study indicates that, independently of the vulnerability to develop amyloid plaques, sleep impairs TREM-dependent microglial functions, which can increase not only the risk to develop Alzheimer’s disease but also many other disorders.
Interestingly, their findings were observed in young mice, suggesting that sleep loss and the associated impaired microglial functions could play an important role early in life and predispose some individuals to develop certain diseases. This suggests that preventive disease strategies must include an adequate regulation of sleep from a young age on, which will involve making changes in healthcare and clinical practice.
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