TREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease

Abstract

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.

Alterations in brain TREM2 and Amyloid‐β levels are associated with neurocognitive impairment in HIV‐infected persons on antiretroviral therapy

“…Moreover, reduced TREM2 is associated with increased autophagy in a mouse model for AD (Ulland et al . ). Hence, the effects of reduced TREM2 on the autophagy pathway and Aβ accumulation in brains of HIV+ individuals warrant future investigation.…”

Opposite microglial activation stages upon loss of PGRN or TREM 2 result in reduced cerebral glucose metabolism

“…Several sequence variants associated with TREM2 cause neurodegeneration via a loss of function (Kleinberger et al , , ; Schlepckow et al , ; Ulland et al , ; Song et al , ). Sequence variants of TREM2 affect a multitude of functions including chemotaxis, migration, survival, binding of phospholipids and ApoE, proliferation, survival, and others (Kleinberger et al , , ; Atagi et al , ; Bailey et al , ; Wang et al , ; Yeh et al , ; Mazaheri et al , ; Ulland et al , ). Strikingly, a loss of TREM2 function locks microglia in a homeostatic state (Krasemann et al , ; Mazaheri et al , ).…”

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

“…More interesting, recent studies found a novel microglia cell type associated with neurodegenerative diseases (DAM cells) using single‐cell RNA‐seq technology, which displayed a unique capability to clear Aβ (Keren‐Shaul, Spinrad, Weiner, Matcovitch‐Natan, & Dvir‐Szternfeld, 2017). Furthermore, another group also found glial cells in patients with AD bearing TREM2 variants, and Trem2 ‐deficient mice have a greater abundance of autophagic vesicle accumulation and an AD‐like pathology (Ulland, Song, Huang, Ulrich, & Sergushichev, 2017). In a mechanical manner, they reported that these specific glial cells are activated sequentially by both Trem2‐independent and Trem2‐dependent pathways, which involved in mTOR‐mediated autophagy and metabolic biosynthetic pathways (Ulland et al., 2017).…”

“…Furthermore, another group also found glial cells in patients with AD bearing TREM2 variants, and Trem2 ‐deficient mice have a greater abundance of autophagic vesicle accumulation and an AD‐like pathology (Ulland, Song, Huang, Ulrich, & Sergushichev, 2017). In a mechanical manner, they reported that these specific glial cells are activated sequentially by both Trem2‐independent and Trem2‐dependent pathways, which involved in mTOR‐mediated autophagy and metabolic biosynthetic pathways (Ulland et al., 2017). These findings together suggest that the disturbance of proteostasis in glial cells mediated by the TREM2‐mTOR axis may lead to further Aβ accumulation.…”