Triggering Receptor Expressed On Myeloid Cells 2 (TREM2)Is A Receptor For β-amyloid Mediating Microglia Function: Implications For Alzheimer’s Disease

Background: Alzheimer’s disease(AD)is a chronic neurodegenerative disease characterized by progressive impairments in memory,executive function and gradual changes in personality and disturbance in daily life.Senile plaques comprising β-amyloid(Aβ)and neurofibrillary tangles(NFTs)made up by hyperphosphorylated tau are the pathological hallmarks of AD.AD is the most common form of dementia,about 5% of people more than 65 years old would suffer from AD and the prevalence increase with age.However,the pathogenesis of AD is largely unknown and currently there is no disease-modifying medications available.The familiar AD is caused by mutations in APP,PSEN1,PSEN2,but it accounts for less than 5% of all AD case.The pathogenesis of more common sporadic AD remains unclear,but the Aβ cascade hypothesis is dominant in the field.Aβis the product of sequential enzyme cleavage of amyloid precursor protein(APP)by β-secreatase and γ-secretase,and constantly aggregates into high molecular weight oligomers and forms the plague in AD context.More and more evidence suggest that soluble Aβ oligomers rather the fibril Aβ in the core of plague are the most toxic species of Aβ and directly impair synapse and neuron function.Triggering receptor expressed on myeloid cells 2(TREM2)is an important receptor mainly expressed in microglia in the brain and is involved in various microglia function such as phagocytosis,migration,cytokine release as well as microglia proliferation and survival.R47 H mutation of TREM2 gene is among the top genetic risk factors for AD,but how TREM2 contributes to AD needs to be elucidated.Previous studies suggest that TREM2 is involved in microglia response to Aβ plague,but the mechanism is unclear.Objective: We proposed that TREM2 can bind to Aβ oligomer and mediate microglia response to Aβ oligomer and Aβ clearance by microglia.TREM2 deficiency might compromise microglia’s response to Aβ and Aβ clearance,thus contribute to AD pathogenesis.Methods: To address our proposal,we employ a battery of binding assay to determine the interaction between TREM2 and Aβ oligomer,then we take advantage of the TREM2 knockout mice model to study whether TREM2/Aβ is needed for microglia’s response to Aβ and Aβ clearance.Results:In our study,we found that TREM2 binds to Aβ oligomer with nonomolar affinity.TREM2 dificiency abolished Aβ induced microglia depolarization,K+ inward current induction,cytokine expression and release,migration,apotosis and morphological changes.TREM2 deficiency also impair Aβ degredation in vitro and in vivo.In addition,TREM2 interaction with its signaling adaptor DAP12 is enhanced by Aβ,regulating downstream signaling such as SYK and GSK3β.Conclusions: Our study show that TREM2 is a receptor of Aβ and is necessary for physiological and AD-related pathological effects associated with Aβ,which would shed light upon the role of TREM2 in AD pathogenesis.