美国斯坦福大学Tony Wyss-Coray小组的近期研究发现，脂滴积累的小胶质细胞在衰老大脑中代表了一种功能失调和促炎状态。该项研究成果于2020年1月20日在线发表在《自然—神经科学》杂志上。

研究人员报道了小鼠和人脑中衰老的小胶质细胞中脂滴的惊人堆积。这些细胞被研究人员称为“脂质液滴积聚小胶质细胞”（LDAM），在吞噬作用方面存在缺陷，可产生高水平的活性氧，并分泌促炎细胞因子。LDAM的RNA测序分析揭示了先天性炎症驱动的转录谱，这与以前报道的小胶质细胞状态不同。无偏倚CRISPR–Cas9筛选确定了脂质滴形成的遗传修饰因子。

令人惊讶地，这些基因中的几种变体，包括前颗粒蛋白（GRN），是人类神经退行性疾病常染色体显性形式的原因。因此，研究人员认为LDAM有助于年龄相关和遗传形式的神经退行性变。

据介绍，小胶质细胞会随着年龄的增长而逐渐激活，并且似乎功能失调，遗传学研究已将这些细胞与越来越多的神经退行性疾病的发病机制联系起来。

附：英文原文

Title: Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain

Author: Julia Marschallinger, Tal Iram, Macy Zardeneta, Song E. Lee, Benoit Lehallier, Michael S. Haney, John V. Pluvinage, Vidhu Mathur, Oliver Hahn, David W. Morgens, Justin Kim, Julia Tevini, Thomas K. Felder, Heimo Wolinski, Carolyn R. Bertozzi, Michael C. Bassik, Ludwig Aigner, Tony Wyss-Coray

Issue&Volume: 2020-01-20

Abstract: Microglia become progressively activated and seemingly dysfunctional with age, and genetic studies have linked these cells to the pathogenesis of a growing number of neurodegenerative diseases. Here we report a striking buildup of lipid droplets in microglia with aging in mouse and human brains. These cells, which we call ‘lipid-droplet-accumulating microglia’ (LDAM), are defective in phagocytosis, produce high levels of reactive oxygen species and secrete proinflammatory cytokines. RNA-sequencing analysis of LDAM revealed a transcriptional profile driven by innate inflammation that is distinct from previously reported microglial states. An unbiased CRISPR–Cas9 screen identified genetic modifiers of lipid droplet formation; surprisingly, variants of several of these genes, including progranulin (GRN), are causes of autosomal-dominant forms of human neurodegenerative diseases. We therefore propose that LDAM contribute to age-related and genetic forms of neurodegeneration.

DOI: 10.1038/s41593-019-0566-1

Source: https://www.nature.com/articles/s41593-019-0566-1