PMID- 35672148
OWN - NLM
STAT- MEDLINE
DCOM- 20220708
LR  - 20240401
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 42
IP  - 27
DP  - 2022 Jul 6
TI  - Microglial mTOR Activation Upregulates Trem2 and Enhances beta-Amyloid Plaque 
      Clearance in the 5XFAD Alzheimer's Disease Model.
PG  - 5294-5313
LID - 10.1523/JNEUROSCI.2427-21.2022 [doi]
AB  - The mechanistic target of rapamycin (mTOR) signaling pathway plays a major role 
      in key cellular processes including metabolism and differentiation; however, the 
      role of mTOR in microglia and its importance in Alzheimer's disease (AD) have 
      remained largely uncharacterized. We report that selective loss of Tsc1, a 
      negative regulator of mTOR, in microglia in mice of both sexes, caused mTOR 
      activation and upregulation of Trem2 with enhanced beta-Amyloid (Abeta) clearance, 
      reduced spine loss, and improved cognitive function in the 5XFAD AD mouse model. 
      Combined loss of Tsc1 and Trem2 in microglia led to reduced Abeta clearance and 
      increased Abeta plaque burden revealing that Trem2 functions downstream of mTOR. 
      Tsc1 mutant microglia showed increased phagocytosis with upregulation of CD68 and 
      Lamp1 lysosomal proteins. In vitro studies using Tsc1-deficient microglia 
      revealed enhanced endocytosis of the lysosomal tracker indicator Green DND-26 
      suggesting increased lysosomal activity. Incubation of Tsc1-deficient microglia 
      with fluorescent-labeled Abeta revealed enhanced Abeta uptake and clearance, which was 
      blunted by rapamycin, an mTOR inhibitor. In vivo treatment of mice of relevant 
      genotypes in the 5XFAD background with rapamycin, affected microglial activity, 
      decreased Trem2 expression and reduced Abeta clearance causing an increase in Abeta 
      plaque burden. Prolonged treatment with rapamycin caused even further reduction 
      of mTOR activity, reduction in Trem2 expression, and increase in Abeta levels. 
      Together, our findings reveal that mTOR signaling in microglia is critically 
      linked to Trem2 regulation and lysosomal biogenesis, and that the upregulation of 
      Trem2 in microglia through mTOR activation could be exploited toward better 
      therapeutic avenues to Abeta-related AD pathologies.SIGNIFICANCE STATEMENT 
      Mechanistic target of rapamycin (mTOR) signaling pathway is a key regulator for 
      major cellular metabolic processes. However, the link between mTOR signaling and 
      Alzheimer's disease (AD) is not well understood. In this study, we provide 
      compelling in vivo evidence that mTOR activation in microglia would benefit 
      beta-Amyloid (Abeta)-related AD pathologies, as it upregulates Trem2, a key receptor 
      for Abeta plaque uptake. Inhibition of mTOR pathway with rapamycin, a 
      well-established immunosuppressant, downregulated Trem2 in microglia and reduced 
      Abeta plaque clearance indicating that mTOR inactivation may be detrimental in 
      Abeta-associated AD patients. This finding will have a significant public health 
      impact and benefit, regarding the usage of rapamycin in AD patients, which we 
      believe will aggravate the Abeta-related AD pathologies.
CI  - Copyright (c) 2022 the authors.
FAU - Shi, Qian
AU  - Shi Q
AD  - Department of Cellular and Integrative Physiology, Long School of Medicine, 
      University of Texas Health Science Center, San Antonio, Texas 78229.
FAU - Chang, Cheng
AU  - Chang C
AD  - Department of Cellular and Integrative Physiology, Long School of Medicine, 
      University of Texas Health Science Center, San Antonio, Texas 78229.
FAU - Saliba, Afaf
AU  - Saliba A
AUID- ORCID: 0000-0003-2576-4069
AD  - Department of Cellular and Integrative Physiology, Long School of Medicine, 
      University of Texas Health Science Center, San Antonio, Texas 78229.
FAU - Bhat, Manzoor A
AU  - Bhat MA
AUID- ORCID: 0000-0003-0989-1498
AD  - Department of Cellular and Integrative Physiology, Long School of Medicine, 
      University of Texas Health Science Center, San Antonio, Texas 78229 
      bhatm@uthscsa.edu.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220607
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Receptors, Immunologic)
RN  - 0 (Trem2 protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - *Alzheimer Disease/metabolism
MH  - Amyloid beta-Peptides/metabolism
MH  - Animals
MH  - Disease Models, Animal
MH  - Female
MH  - Male
MH  - *Membrane Glycoproteins/genetics/metabolism
MH  - Mice
MH  - Mice, Transgenic
MH  - Microglia/metabolism
MH  - *Plaque, Amyloid/pathology
MH  - *Receptors, Immunologic/genetics/metabolism
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC9270922
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - Trem2
OT  - mTOR
OT  - microglia
OT  - rapamycin
OT  - beta-amyloid
EDAT- 2022/06/08 06:00
MHDA- 2022/07/09 06:00
PMCR- 2023/01/06
CRDT- 2022/06/07 21:22
PHST- 2021/12/11 00:00 [received]
PHST- 2022/05/04 00:00 [revised]
PHST- 2022/05/05 00:00 [accepted]
PHST- 2022/06/08 06:00 [pubmed]
PHST- 2022/07/09 06:00 [medline]
PHST- 2022/06/07 21:22 [entrez]
PHST- 2023/01/06 00:00 [pmc-release]
AID - JNEUROSCI.2427-21.2022 [pii]
AID - JN-RM-2427-21 [pii]
AID - 10.1523/JNEUROSCI.2427-21.2022 [doi]
PST - ppublish
SO  - J Neurosci. 2022 Jul 6;42(27):5294-5313. doi: 10.1523/JNEUROSCI.2427-21.2022. 
      Epub 2022 Jun 7.