阿尔茨海默病风险基因APOE4的损伤可逆转

西奈山医学院研究人员发现，阿尔茨海默病风险基因APOE4导致的脑损伤过程可能存在逆转的可能。1这一发现基于两项研究，分别发表于2026年9月24日的《细胞》和《细胞干细胞》杂志第33卷第9期。1

研究表明，APOE4通过两种主要机制对脑造成损害。1一方面，该基因会改变脑血管周围周细胞的行为，促使其转化为产生疤痕组织的成纤维细胞样细胞，从而导致血管纤维化。1另一方面，APOE4导致胆固醇在星形胶质细胞中积累，干扰了这些细胞的溶酶体清除α-突触核蛋白等有害蛋白的能力。1

关键的是，研究发现这些损伤具有可逆性。1通过阻断TGF-β信号传导，研究人员能够恢复周细胞覆盖，减少纤维化现象，并降低血管周围淀粉样蛋白的积累。1

研究团队还建立了一个名为miBrains的平台，该平台基于干细胞衍生的人脑组织技术开发，可加速阿尔茨海默病、帕金森病等神经退行性疾病的治疗靶点发现。1该研究得到了美国国立卫生研究院和美国宇航局等机构的资助。1

Researchers at Mount Sinai School of Medicine have identified how the Alzheimer's disease risk gene APOE4 damages the brain through mechanisms that may be reversible 1. Two studies published in Cell and Cell Stem Cell on September 24, 2026, reveal that APOE4 impairs cerebral blood vessels and disrupts the cellular system responsible for clearing harmful proteins, but blocking TGF-β signaling can restore these damaged pathways 1.

The research demonstrates that APOE4 alters the behavior of pericytes, specialized cells that support blood vessels, causing them to transform into fibroblast-like cells that produce scar tissue 1. When TGF-β signaling is blocked, pericyte coverage can be restored and fibrosis and perivascular amyloid accumulation are reduced 1. Additionally, the studies show that APOE4 causes cholesterol to accumulate in astrocytes, impairing their lysosomal ability to clear alpha-synuclein, a protein associated with neurodegeneration 1.

To accelerate the discovery of therapeutic targets, the research team established miBrains, a platform based on stem cell-derived human brain tissue that can be used to study Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions 1. Over 7 million older adults in the United States have Alzheimer's disease 1. The research was supported by funding from NASA, the National Institutes of Health, and other institutions 1.