Abstract
Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor genetically linked to the risk for Alzheimer’s disease (AD). A proteolytic product, soluble TREM2 (sTREM2), is abundant in the cerebrospinal fluid and its levels positively correlate with neuronal injury markers. To gain insights into the pathological roles of sTREM2, we studied sTREM2 in the brain of 5xFAD mice, a model of AD, by direct stereotaxic injection of recombinant sTREM2 protein or by adeno-associated virus (AAV)-mediated expression. We found that sTREM2 reduces amyloid plaque load and rescues functional deficits of spatial memory and long-term potentiation. Importantly, sTREM2 enhances microglial proliferation, migration, clustering in the vicinity of amyloid plaques and the uptake and degradation of Aβ. Depletion of microglia abolishes the neuroprotective effects of sTREM2. Our study demonstrates a protective role of sTREM2 against amyloid pathology and related toxicity and suggests that increasing sTREM2 can be explored for AD therapy.
Highlights
Microglia are effective phagocytes in the central nervous system (CNS) for the uptake and proteolytic clearance of both soluble and fibrillary forms of Aβ6
We found that soluble TREM2 (sTREM2) reduces amyloid-β (Aβ) pathology and improves cognitive and synaptic functions by modulating microglial activity in 5×FAD mouse model, providing a rationale that sTREM2 can be explored for Alzheimer’s disease (AD) therapy
It has been widely acknowledged that the cerebrospinal fluid (CSF) levels of sTREM2 are elevated in AD, it remains unknown how sTREM2 impacts the amyloid pathology and microglial behaviors in the disease context
Summary
Microglia are effective phagocytes in the central nervous system (CNS) for the uptake and proteolytic clearance of both soluble and fibrillary forms of Aβ6. Studies have found that microglial cells are clustered around amyloid plaques in the brain of AD patients[7,8] and AD mouse models[9]. TREM2 plays important roles in microglial phagocytosis of apoptotic neurons, damaged myelin, and amyloid plaques[21,28]. Whether sTREM2 has protective effects against amyloid pathology and the related synaptic toxicity remains to be defined. We explored the effects of sTREM2 on pathological phenotypes in 5×FAD mouse model by direct stereotaxic injection of recombinant sTREM2 protein or by an adenovirus-associated virus (AAV)-mediated expression strategy. We found that sTREM2 reduces amyloid-β (Aβ) pathology and improves cognitive and synaptic functions by modulating microglial activity in 5×FAD mouse model, providing a rationale that sTREM2 can be explored for AD therapy
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