TREM1 disrupts myeloid bioenergetics and cognitive function in aging and Alzheimer’s disease models

Abstract

SUMMARYHuman genetics implicate defective myeloid responses in the development of late onset, age-associated Alzheimer’s disease (AD). Aging is characterized by a decline in myeloid metabolism that triggers maladaptive, neurotoxic immune responses. TREM1 is an amplifier of pro-inflammatory myeloid responses, and here we find thatTrem1deficiency prevents age-dependent changes in myeloid metabolism, inflammation, and hippocampal memory function.Trem1deficiency rescues age-associated declines in ribose-5P, a glycolytic intermediate and the precursor for purine, pyrimidine, and NAD+biosynthesis. In vitro,Trem1deficient microglia are resistant to bioenergetic changes induced by amyloid-ß42oligomers (Aß42), suggesting that Aß42stimulation disrupts homeostatic microglial metabolism and immune function via TREM1. In the 5XFAD model of amyloid accumulation,Trem1haploinsufficiency prevents spatial memory loss, preserves homeostatic microglial morphology, and reduces neuritic dystrophy independent of amyloid accumulation or changes in the disease-associated microglial transcriptomic signature. In agingAPPSwemice,Trem1deficiency restores synaptic mitochondrial function and cerebral glucose uptake and prevents hippocampal memory decline. In post-mortem human brain, microglial TREM1 expression increases with clinical and neuropathological severity. Thus, TREM1-mediated disruption of myeloid metabolism, both in the periphery and brain, promotes cognitive decline in aging and amyloid accumulation, two major risk factors for AD development.