脂肪がアルツハイマー病における脳の免疫防御機構を無効化する仕組みを解明(Purdue-led study shows how fat disables the brain’s immune shield in Alzheimer’s disease)

2025-09-09 パデュー大学

<関連情報>

• https://www.purdue.edu/newsroom/2025/Q3/purdue-led-study-shows-how-fat-disables-the-brains-immune-shield-in-alzheimers-disease/
• https://www.cell.com/immunity/abstract/S1074-7613(25)00192-X
• https://www.nature.com/articles/s41586-021-03960-y

アルツハイマー病におけるアミロイドβによるDGAT2酵素を介した脂質滴媒介性ミクログリア機能障害の誘導 Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease

Priya Prakash ∙ Palak Manchanda ∙ Evi Paouri ∙ … ∙ Chi Zhang ∙ Dimitrios Davalos ∙ Gaurav Chopra
Immunity  Published:May 19, 2025
DOI:https://doi.org/10.1016/j.immuni.2025.04.029

Graphical abstract

Highlights

• Aβ drives microglial lipid droplet buildup via DGAT2-mediated conversion of FFAs to TGs
• Microglial lipid droplets and DGAT2 are elevated in AD mouse models and human brains
• Lipid-laden, DGAT2^high microglia show impaired Aβ phagocytosis and neuronal damage
• DGAT2 degradation restores Aβ uptake and reduces amyloid plaques and dystrophic neurons

Summary

Microglial phagocytosis genes have been linked to increased risk for Alzheimer’s disease (AD), but the mechanisms translating genetic association to cellular dysfunction remain unknown. Here, we showed that microglia formed lipid droplets (LDs) upon amyloid-β (Aβ) exposure and that LD loads increased with proximity to amyloid plaques in brains from individuals with AD and the 5xFAD mouse model. LD-laden microglia exhibited defects in Aβ phagocytosis, and unbiased lipidomic analyses identified a parallel decrease in free fatty acids (FFAs) and increase in triacylglycerols (TGs) as the key metabolic transition underlying LD formation. Diacylglycerol O-acyltransferase 2 (DGAT2)—a key enzyme that converts FFAs to TGs—promoted microglial LD formation and was increased in mouse 5xFAD and human AD brains. Pharmacologically targeting DGAT2 improved microglial uptake of Aβ and reduced plaque load and neuronal damage in 5xFAD mice. These findings identify a lipid-mediated mechanism underlying microglial dysfunction that could become a therapeutic target for AD.

神経毒性反応性アストロサイトによる飽和脂質を介した細胞死の誘導 Neurotoxic reactive astrocytes induce cell death via saturated lipids

Kevin A. Guttenplan,Maya K. Weigel,Priya Prakash,Prageeth R. Wijewardhane,Philip Hasel,Uriel Rufen-Blanchette,Alexandra E. Münch,Jacob A. Blum,Jonathan Fine,Mikaela C. Neal,Kimberley D. Bruce,Aaron D. Gitler,Gaurav Chopra,Shane A. Liddelow & Ben A. Barres
Nature  Published:06 October 2021
DOI:https://doi.org/10.1038/s41586-021-03960-y

Abstract

Astrocytes regulate the response of the central nervous system to disease and injury and have been hypothesized to actively kill neurons in neurodegenerative disease^1,2,3,4,5,6. Here we report an approach to isolate one component of the long-sought astrocyte-derived toxic factor^5,6. Notably, instead of a protein, saturated lipids contained in APOE and APOJ lipoparticles mediate astrocyte-induced toxicity. Eliminating the formation of long-chain saturated lipids by astrocyte-specific knockout of the saturated lipid synthesis enzyme ELOVL1 mitigates astrocyte-mediated toxicity in vitro as well as in a model of acute axonal injury in vivo. These results suggest a mechanism by which astrocytes kill cells in the central nervous system.