TREM2 maintains microglial metabolic fitness in Alzheimer’s disease

By Tyler K. Ulland, Wilbur M Song, S. C. Huang, Jason D. Ulrich, Alexey A. Sergushichev, W. Beatty, A. Loboda, Yingyue Zhou, Nigel J. Cairns, Amal Kambal and 9 more. Cell, 2017

1,052 citations recorded by the source corpus.

Summary Elevated risk of developing Alzheimer’s disease (AD) is associated with hypomorphic variants of TREM2, a surface receptor required for microglial responses to neurodegeneration, including proliferation, survival, clustering and phagocytosis. How TREM2 promotes such diverse responses is unknown. Here, we find that microglia in AD patients carrying TREM2 risk variants and TREM2-deficient mice with AD-like pathology have abundant autophagic vesicles, as do TREM2-deficient macrophages under growth factor limitation or ER stress. Combined metabolomics and RNA-seq linked this anomalous autophagy to defective mTOR signaling, which affects ATP levels and biosynthetic pathways. Metabolic derailment and autophagy were offset in vitro through Dectin-1, a receptor that elicits TREM2-like intracellular signals, and cyclocreatine, a creatine analog that can supply ATP. Dietary cyclocreatine tempered autophagy, restored microglial clustering around plaques, and decreased plaque-adjacent neuronal dystrophy in TREM2-deficient mice with amyloid-β pathology. Thus, TREM2 enables microglial responses during AD by sustaining cellular energetic and biosynthetic metabolism.

Subfields: Complementary and alternative medicine, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/0604b7cf92305b539c24082a3f1a42d13b80ac96

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Neurology

1. M. Colonna
2. Florent Ginhoux
3. M. Hasegawa

In Physiology

1. M. Colonna
2. Florent Ginhoux
3. Mitchell A. Lazar
4. Eran Elinav
5. Barry M. Popkin
6. Haiming Cao

Citations in the corpus

• Microglia in Alzheimer’s disease (2018, background): “A recent study suggested that the multifaceted microglial dysfunction observed in TREM2-deficient mice with β-amyloid pathology could stem from impaired mTOR signaling and a metabolic deficit (Ulland et al., 2017).”
• Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer's Disease (2018, background): “Therefore, the TREM2-ApoE pathway is important for facilitating the microglial response to damage in the brain, and a functional consequence of activation of the TREM2-ApoE pathway is that microglia lose the ability to regulate brain homeostasis (Krasemann et al., 2017; Ulland et al., 2017).”
• Microglia states and nomenclature: A field at its crossroads (2022, neutral): “58,59,85,121 How the TREM2 receptor drives the DAM transcriptional phenotype remains unclear, although the TREM2-ApoE signaling pathway is necessary for the switch from homeostatic to MGnD. 59 Further investigations are required to fully elucidate the role of TREM2.”
• Lipid-associated macrophages control metabolic homeostasis in a Trem2-dependent manner (2019, background): “This approach revealed a strong enrichment of LAM-expressed genes in pathways related to phago- and endocytosis as well as lipid metabolism (Figures 3G, 3H, S5C, and S5D), many of which were shared between mouse and human (Figures 3G and 3H), in line with previous reports on the function of Trem2 as”