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

Autor: Wilson EN; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA., Wang C; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Swarovski MS; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Zera KA; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Ennerfelt HE; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Wang Q; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Chaney A; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.; Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA., Gauba E; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Ramos Benitez JA; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Le Guen Y; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Minhas PS; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Panchal M; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Tan YJ; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Blacher E; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., A Iweka C; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Cropper H; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.; Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA., Jain P; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.; Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA., Liu Q; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Mehta SS; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Zuckerman AJ; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Xin M; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Umans J; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Huang J; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Durairaj AS; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Serrano GE; Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA., Beach TG; Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA., Greicius MD; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA., James ML; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.; Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA., Buckwalter MS; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.; Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA., McReynolds MR; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.; Department of Chemistry, Princeton University, Princeton, NJ, USA.; Department of Biochemistry and Molecular Biology, Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, USA., Rabinowitz JD; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.; Department of Chemistry, Princeton University, Princeton, NJ, USA., Andreasson KI; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA. kandreas@stanford.edu.; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA. kandreas@stanford.edu.; Chan Zuckerberg Biohub, San Francisco, CA, USA. kandreas@stanford.edu.
Jazyk: angličtina
Zdroj: Nature neuroscience [Nat Neurosci] 2024 May; Vol. 27 (5), pp. 873-885. Date of Electronic Publication: 2024 Mar 27.
DOI: 10.1038/s41593-024-01610-w
Abstrakt: 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-β 42 oligomer-induced bioenergetic changes, suggesting that amyloid-β 42 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 APP Swe 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.
(© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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