TY - JOUR
T1 - TREM1 disrupts myeloid bioenergetics and cognitive function in aging and Alzheimer disease mouse models
AU - Wilson, Edward N.
AU - Wang, Congcong
AU - Swarovski, Michelle S.
AU - Zera, Kristy A.
AU - Ennerfelt, Hannah E.
AU - Wang, Qian
AU - Chaney, Aisling
AU - Gauba, Esha
AU - Ramos Benitez, Javier A.
AU - Le Guen, Yann
AU - Minhas, Paras S.
AU - Panchal, Maharshi
AU - Tan, Yuting J.
AU - Blacher, Eran
AU - A. Iweka, Chinyere
AU - Cropper, Haley
AU - Jain, Poorva
AU - Liu, Qingkun
AU - Mehta, Swapnil S.
AU - Zuckerman, Abigail J.
AU - Xin, Matthew
AU - Umans, Jacob
AU - Huang, Jolie
AU - Durairaj, Aarooran S.
AU - Serrano, Geidy E.
AU - Beach, Thomas G.
AU - Greicius, Michael D.
AU - James, Michelle L.
AU - Buckwalter, Marion S.
AU - McReynolds, Melanie R.
AU - Rabinowitz, Joshua D.
AU - Andreasson, Katrin I.
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.
PY - 2024/5
Y1 - 2024/5
N2 - 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.
AB - 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.
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U2 - 10.1038/s41593-024-01610-w
DO - 10.1038/s41593-024-01610-w
M3 - Article
C2 - 38539014
AN - SCOPUS:85188839920
SN - 1097-6256
VL - 27
SP - 873
EP - 885
JO - Nature neuroscience
JF - Nature neuroscience
IS - 5
ER -