Microglial mTOR Activation Upregulates Trem2 and Enhances β-Amyloid Plaque Clearance in the <i>5XFAD</i> Alzheimer's Disease Model

Shi, Qian; Chen, Cheng; Saliba, Afaf; Bhat, Manzoor A.

doi:10.1523/jneurosci.2427-21.2022

Cited by 58 publications

(34 citation statements)

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“…We examined the levels of autophagy (LC3 and p62; Le Guerroué et al., 2023) and lysosomes (CD68 and Lamp1; Shi et al., 2022) in microglia, as myelin debris is mainly degraded through the autophagic‐lysosomal pathway following phagocytosis (Qin et al., 2023). Interestingly, significant activation of autophagy and lysosomes in microglia after BCAS were observed, peaked at 1 month (Figure 2a–d).…”

Section: Resultsmentioning

confidence: 99%

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Trem2 deficiency attenuates microglial phagocytosis and autophagic‐lysosomal activation in white matter hypoperfusion

Pang,

Chu,

Zhou

et al. 2023

Journal of Neurochemistry

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Chronic cerebral hypoperfusion leads to sustained demyelination and a unique response of microglia. Triggering receptor expressed on myeloid cells 2 (Trem2), which is expressed exclusively on microglia in the central nervous system (CNS), plays an essential role in microglial response in various CNS disorders. However, the specific role of Trem2 in chronic cerebral hypoperfusion has not been elucidated. In this study, we investigated the specific role of Trem2 in a mouse model of chronic cerebral hypoperfusion induced by bilateral carotid artery stenosis (BCAS). Our results showed that chronic hypoperfusion induced white matter demyelination, microglial phagocytosis, and activation of the microglial autophagic‐lysosomal pathway, accompanied by an increase in Trem2 expression. After Trem2 knockout, we observed attenuation of white matter lesions and microglial response. Trem2 deficiency also suppressed microglial phagocytosis and relieved activation of the autophagic‐lysosomal pathway, leading to microglial polarization towards anti‐inflammatory and homeostatic phenotypes. Furthermore, Trem2 knockout inhibited lipid droplet accumulation in microglia in vitro. Collectively, these findings suggest that Trem2 deficiency ameliorated microglial phagocytosis and autophagic‐lysosomal activation in hypoperfusion‐induced white matter injury, and could be a promising target for the treatment of chronic cerebral hypoperfusion.image

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Section: Resultsmentioning

confidence: 99%

“…We examined the levels of autophagy (LC3 and p62; Le Guerroué et al, 2023) and lysosomes (CD68 and Lamp1; Shi et al, 2022) in microglia, as myelin debris is mainly degraded through the autophagiclysosomal pathway following phagocytosis (Qin et al, 2023).…”

Section: White Matter Demyelination and Microglial Response Induced B...mentioning

confidence: 99%

Trem2 deficiency attenuates microglial phagocytosis and autophagic‐lysosomal activation in white matter hypoperfusion

Pang,

Chu,

Zhou

et al. 2023

Journal of Neurochemistry

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“…Antigen presentation pathway was upregulated in TREM2‐R47H‐overexpressing AD model mice at the amyloid growth period, which aggravated amyloid burden (Zhao et al, 2022), while ribosome dysfunction is a premature event in AD (Ding et al, 2005). Ribosome biogenesis, is fueled by mTOR signaling in growing cells (O'Farrell et al, 1998) and microglial mTOR activation increases Aβ‐plaque clearance in AD model mice (Shi et al, 2022). Hence, altered biological process branching by EC senescence functions critically in the attenuation of AD pathology in APP/PS1;TERF2DN mice.…”

Section: Discussionmentioning

confidence: 99%

Endothelial senescence alleviates cognitive impairment in a mouse model of Alzheimer's disease

Horibe,

Emoto,

Mizoguchi

et al. 2023

Glia

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Alzheimer's disease (AD) is among the most prevalent age‐related neurodegenerative diseases. Endothelial cell (EC) senescence was discovered in the AD brain, but its function in AD pathogenesis was unidentified. Here we created an AD mouse model with EC senescence (APP/PS1;TERF2DN mice) by intercrossing APP/PS1 mice with Tie2 promoter‐driven dominant negative telomeric repeat‐binding factor 2 transgenic mice (TERF2DN‐Tg mice). We evaluated cognitive functions and AD brain pathology in APP/PS1;TERF2DN mice. Surprisingly, compared with the control APP/PS1 mice, APP/PS1;TERF2DN mice demonstrated the attenuation of cognitive impairment and amyloid‐β (Aβ) pathology, accompanied by the compaction of Aβ plaques with increased microglial coverage and reduced neurite dystrophy. Moreover, we evaluated whether EC senescence could affect microglial morphology and phagocytosis of Aβ. Compared with wild‐type mice, microglia in TERF2DN‐Tg mice display increased numbers of endpoints (a morphometric parameter to quantify the number of processes) and Aβ phagocytosis and related gene expression. Single‐cell RNA‐sequencing analysis showed that compared with APP/PS1 mouse microglia, APP/PS1;TERF2DN mouse microglia displayed a modest decline in disease‐associated microglia, accompanied by an altered direction of biological process branching from antigen synthesis and arrangement to ribonucleoprotein complex biogenesis. Our outcomes indicate that EC senescence alters microglia toward a protective phenotype with a rise in phagocytic and barrier roles, and may offer a clue to create a novel preventive/therapeutic method to treat AD.

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“…69 On the other hand, different concentrations of Aβ could result in differential effects on mTOR signaling. 145 Shi et al 158 Although we believe that the controversial findings may stem from the different AD mouse models use, there may be multiple factors at play in the controversial findings. Low mTORC1 signaling is likely to be desirable in healthy state or early progression of the disease, while high levels are likely to be needed for brain health maintenance and microglial homeostasis at later stages.…”

Section: Ther Apeuti C P Otentialmentioning

confidence: 97%

mTOR signaling and Alzheimer's disease: What we know and where we are?

Davoody,

Asgari Taei,

Khodabakhsh

et al. 2023

CNS Neurosci Ther

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Despite the great body of research done on Alzheimer's disease, the underlying mechanisms have not been vividly investigated. To date, the accumulation of amyloid‐beta plaques and tau tangles constitutes the hallmark of the disease; however, dysregulation of the mammalian target of rapamycin (mTOR) seems to be significantly involved in the pathogenesis of the disease as well. mTOR, as a serine–threonine protein kinase, previously known for controlling many cellular functions such as cell size, autophagy, and metabolism. In this regard, mammalian target of rapamycin complex 1 (mTORC1) may leave anti‐aging impacts by robustly inhibiting autophagy, a mechanism that inhibits the accumulation of damaged protein aggregate and dysfunctional organelles. Formation and aggregation of neurofibrillary tangles and amyloid‐beta plaques seem to be significantly regulated by mTOR signaling. Understanding the underlying mechanisms and connection between mTOR signaling and AD may suggest conducting clinical trials assessing the efficacy of rapamycin, as an mTOR inhibitor drug, in managing AD or may help develop other medications. In this literature review, we aim to elaborate mTOR signaling network mainly in the brain, point to gaps of knowledge, and define how and in which ways mTOR signaling can be connected with AD pathogenesis and symptoms.

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Microglial mTOR Activation Upregulates Trem2 and Enhances β-Amyloid Plaque Clearance in the 5XFAD Alzheimer's Disease Model

Cited by 58 publications

References 100 publications

Trem2 deficiency attenuates microglial phagocytosis and autophagic‐lysosomal activation in white matter hypoperfusion

Trem2 deficiency attenuates microglial phagocytosis and autophagic‐lysosomal activation in white matter hypoperfusion

Endothelial senescence alleviates cognitive impairment in a mouse model of Alzheimer's disease

mTOR signaling and Alzheimer's disease: What we know and where we are?

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