Vps35‐dependent recycling of Trem2 regulates microglial function

Abstract

Triggering receptor expressed on myeloid cells 2 (Trem2), an immune-modulatory receptor, is preferentially expressed in microglia of central nervous system. Trem2 might be involved in the development of Alzheimer's disease (AD) through regulating the inflammatory responses and phagocytosis of microglia. However, the intracellular trafficking of Trem2 remains unclear. In this study, we showed that Trem2 in the plasma membrane underwent endocytosis and recycling. Trem2 is internalized in a clathrin-dependent manner and then recycled back to the plasma membrane through vacuolar protein sorting 35 (Vps35), the key component of cargo recognition core of retromer complex, but not Rab11. When Vps35 is knocked down, Trem2 accumulated in the lysosomes but was not degraded. More importantly, Vps35 deficiency leads to excessive lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) expression and IL-6 production, which can be abolished by Trem2 overexpression. Furthermore, R47HTrem2, an AD-associated mutant, failed to interact with Vps35 and became unstable compared with wild-type Trem2. Our study suggests that Vps35/retromer is responsible for recycling of Trem2 in the regulation of microglial function such as proinflammatory responses, whereas R47H mutation impairs Trem2 trafficking, which might contribute to AD. K E Y W O R D SAlzheimer's disease, microglia, receptor recycling, retromer, Trem2, Vps35

To degrade or not to degrade: mechanisms and significance of endocytic recycling

“…interacts with β-amyloid precursor protein (APP) and its aberrant recycling influences recycling of APP, whereas TREM2 is localised to the cell surface of microglia [G] and binds extracellular β-amyloid, thereby promoting its clearance and preventing spreading 216 .…”

Endosomal Traffic Jams Represent a Pathogenic Hub and Therapeutic Target in Alzheimer’s Disease

“…Besides mediating synaptic toxicity and exosomal spread of disease, we briefly note that some studies have linked retromer trafficking (Small and Petsko, 2015), BIN1 (Calafate et al, 2016; Chapuis et al, 2013; Zhou et al, 2014), and CD2AP (Shulman et al, 2014) to tau pathology, potentially independent of amyloid, and retromer has also been linked to immune response genes, such as TREM2, that are phagocytic receptors trafficked in microglia (Lucin et al, 2013; Small and Petsko, 2015; Sole-Domenech et al, 2016; Yin et al, 2016). A detailed discussion of these additional pathophysiological links is considered outside the scope of this Opinion.…”

Coupling of terminal differentiation deficit with neurodegenerative pathology in Vps35-deficient pyramidal neurons

“…Vps35-deficient mice exhibit partial AD-or PD-relevant deficits [10,11,14] and overexpressing Vps35 fully recovers the AD phenotype in 3xTg mice [15]. In addition, retromer cargo proteins including APP [16], TREM2 [17], and sortilin1-related receptor (SorLA) [18] are genetic risk factors for AD. Interestingly, sortilin1 (Sort1) and SorLA are members of vacuolar protein sorting ten family receptors.…”