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

Edward N. Wilson, Congcong Wang, Michelle S. Swarovski, Kristy A. Zera, Hannah E. Ennerfelt, Qian Wang, Aisling Chaney, Esha Gauba, Javier A. Ramos Benitez, Yann Le Guen, Paras S. Minhas, Maharshi Panchal, Yuting J. Tan, Eran Blacher, Chinyere A. Iweka, Haley Cropper, Poorva Jain, Qingkun Liu, Swapnil S. Mehta, Abigail J. ZuckermanMatthew Xin, Jacob Umans, Jolie Huang, Aarooran S. Durairaj, Geidy E. Serrano, Thomas G. Beach, Michael D. Greicius, Michelle L. James, Marion S. Buckwalter, Melanie R. McReynolds, Joshua D. Rabinowitz, Katrin I. Andreasson

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Human genetics implicate defective myeloid responses in the development of late-onset Alzheimer disease. A decline in peripheral and brain myeloid metabolism, triggering maladaptive immune responses, is a feature of aging. The role of TREM1, a pro-inflammatory factor, in neurodegenerative diseases is unclear. Here we show that Trem1 deficiency prevents age-dependent changes in myeloid metabolism, inflammation and hippocampal memory function in mice. Trem1 deficiency rescues age-associated declines in ribose 5-phosphate. In vitro, Trem1-deficient microglia are resistant to amyloid-β42 oligomer-induced bioenergetic changes, suggesting that amyloid-β42 oligomer stimulation disrupts homeostatic microglial metabolism and immune function via TREM1. In the 5XFAD mouse model, Trem1 haploinsufficiency prevents spatial memory loss, preserves homeostatic microglial morphology, and reduces neuritic dystrophy and changes in the disease-associated microglial transcriptomic signature. In aging APPSwe mice, Trem1 deficiency prevents hippocampal memory decline while restoring synaptic mitochondrial function and cerebral glucose uptake. In postmortem Alzheimer disease brain, TREM1 colocalizes with Iba1+ cells around amyloid plaques and its expression is associated with Alzheimer disease clinical and neuropathological severity. Our results suggest that TREM1 promotes cognitive decline in aging and in the context of amyloid pathology.

Original languageEnglish (US)
Pages (from-to)873-885
Number of pages13
JournalNature neuroscience
Volume27
Issue number5
DOIs
StatePublished - May 2024

All Science Journal Classification (ASJC) codes

  • General Neuroscience

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