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Correlative Light and Electron Microscopy to Study Microglial Interactions with β-Amyloid Plaques
Published on: June 1, 2016
Microglial mTOR Activation Upregulates Trem2 and Enhances β-Amyloid Plaque Clearance in the 5XFAD Alzheimer's Disease
Qian Shi1, Cheng Chang1, Afaf Saliba1
1Department of Cellular and Integrative Physiology, Long School of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229.
Abstract:
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 β-Amyloid (Aβ) 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 Aβ clearance and increased Aβ 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 Aβ revealed enhanced Aβ 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 Aβ clearance causing an increase in Aβ plaque burden. Prolonged treatment with rapamycin caused even further reduction of mTOR activity, reduction in Trem2 expression, and increase in Aβ 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 Aβ-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 β-Amyloid (Aβ)-related AD pathologies, as it upregulates Trem2, a key receptor for Aβ plaque uptake. Inhibition of mTOR pathway with rapamycin, a well-established immunosuppressant, downregulated Trem2 in microglia and reduced Aβ plaque clearance indicating that mTOR inactivation may be detrimental in Aβ-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 Aβ-related AD pathologies.
Insights
Activating the mTOR pathway in microglia enhances Alzheimer's disease (AD) pathology clearance by upregulating Trem2. Inhibiting mTOR with rapamycin worsens AD by reducing Trem2 and Aβ clearance.
Area of Science:
- Neuroscience
- Cell Biology
- Immunology
Background:
- The mechanistic target of rapamycin (mTOR) pathway regulates critical cellular functions, but its role in microglia and Alzheimer's disease (AD) is unclear.
- Microglia, the brain's immune cells, are increasingly implicated in AD pathogenesis.
- Trem2 is a microglial receptor crucial for clearing amyloid-beta (Aβ) plaques.
Purpose of the Study:
- To investigate the role of mTOR signaling in microglia within the context of Alzheimer's disease.
- To determine the impact of mTOR activation and inhibition on microglial function and Aβ pathology.
- To explore the relationship between mTOR, Trem2, and lysosomal activity in AD.
Main Methods:
- Utilized Tsc1 conditional knockout mice to selectively activate mTOR in microglia.
- Administered rapamycin (mTOR inhibitor) to 5XFAD AD mouse models.
- Performed in vitro studies with Tsc1-deficient microglia to assess phagocytosis and lysosomal activity.
- Quantified Aβ plaque burden, spine loss, and cognitive function in mouse models.
Main Results:
- Microglial mTOR activation via Tsc1 deletion enhanced Aβ clearance, reduced spine loss, and improved cognition in 5XFAD mice.
- mTOR activation upregulated Trem2 expression in microglia, which was found to function downstream of mTOR.
- Tsc1-deficient microglia exhibited increased phagocytosis, lysosomal activity, and Aβ uptake, effects blunted by rapamycin.
- Rapamycin treatment in 5XFAD mice reduced microglial activity, decreased Trem2 expression, and exacerbated Aβ plaque burden.
Conclusions:
- mTOR signaling in microglia is essential for Trem2 regulation and lysosomal biogenesis, impacting Aβ clearance.
- Activating microglial mTOR may offer a therapeutic strategy for Aβ-related AD pathologies by enhancing Trem2-mediated clearance.
- Inhibiting mTOR with rapamycin could be detrimental in AD patients, potentially worsening Aβ pathology.
