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撰文丨nagashi
Editor丨Wang Duoyu typesetting丨Shui Chengwen
In 1906, the German physician Alois Alzheimer first reported a patient with progressive dementia who sometimes treated him like a stranger and sometimes screamed at him and became insane. This was later named Alzheimer's disease.
Alois Alzheimer dissected the patient's brain after his death and found that the entire brain was covered with dark plaques between neurons, and in the dead neurons there were fibers tangled together like threads. Since then, plaques and tangles have become important for the diagnosis of Alzheimer's disease. The vast majority of drug development aimed at preventing, slowing, and halting the progression of Alzheimer's disease has focused on reducing or eliminating these plaques and tangles. But as we can see, very few of these drugs have been successful.
In fact, in addition to plaques and tangles in the patient's brain, Alois Alzheimer noticed the accumulation of fat droplets in the patient's brain cells (microglia). However, for more than 100 years since, the pathological hallmark of fat droplet accumulation in microglia in Alzheimer's disease patients has been largely overlooked.
2024年3月13日，斯坦福大学医学院 Tony Wyss-Coray 团队在国际顶尖学术期刊 Nature 上发表了题为：APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia 的研究论文。
The study suggests that the underlying cause of Alzheimer's disease may be the accumulation of fat in brain cells. APOE, especially APOE4, is closely related to the abnormal accumulation of lipid droplets in microglia of Alzheimer's disease, which may open up a new path for the prevention and treatment of Alzheimer's disease.
With the intensification of the global aging wave, the incidence of Alzheimer's disease (AD), commonly known as Alzheimer's disease, is increasing year by year.
Notably, several genetic risk factors for Alzheimer's disease are associated with lipid metabolism, many of which are highly expressed in the patient's glial cells. However, the link between glial lipid metabolism and Alzheimer's disease pathology is still poorly understood.
In the latest study, published in Nature, the research team focused on the APOE gene. Previous studies have shown that the APOE gene encodes the protein involved in transporting fat droplets to brain cells, and it has a total of 6 different genotypes, namely, APOE4/E4, APOE4/E3, APOE4/E2, APOE3/E3, APOE3/E2, and APOE2/E2, of which the first two genotypes are associated with a high incidence of Alzheimer's disease.
Lipid accumulation is associated with pathological changes in Alzheimer's disease
The research team investigated whether the APOE variant increases the risk of Alzheimer's disease. To find out, they conducted a series of experiments:
In the first experiment, the research team collected brain tissue samples from patients with Alzheimer's disease who had dual copies of APOE4 or APOE3. Using single-cell RNA sequencing (snRNA-seq) to identify differential protein expression in the patient's brain cells, they discovered a lipid droplet-associated enzyme called ACSL1 that promotes the entry of fat droplets into brain cells. ACSL1 is highly expressed in brain cells of APOE4 gene carriers, and ACSL1-positive microglia are most abundant in patients with APOE4/4 genotype Alzheimer's disease.
Alzheimer's disease microglia have a lipid transcriptional status defined by ACSL1
In another experiment, the research team induced the accumulation of β-amyloid (Aβ) in pluripotent stem cell (hiPSC)-derived microglia (iMG). They found that Aβ induces ACSL1 expression, triglyceride synthesis, and lipid droplet accumulation in an APOE-dependent manner.
After Aβ stimulation, iMG increased ACSL1 expression, triglyceride synthesis, and lipid droplet accumulation
In simple terms, in people who carry the APOE4 or APOE3 variants, Aβ causes their brain cells to accumulate more fat. In contrast, lipid droplet-rich microglial conditioned media also lead to tau phosphorylation and neurotoxicity in an APOE-dependent manner. These findings suggest that the accumulation of β-amyloid in the brains of APOE4/APOE3 carriers promotes the entry of fat into brain cells, thereby exacerbating the occurrence and development of Alzheimer's disease.
Study pattern diagrams
Overall, the study, published in Nature, found that the APOE4 genotype promotes the transition of microglia to an evolutionarily conserved, maladapted, and destructive lipid droplet accumulation (LDAM) state in response to innate immune triggers including β-amyloid (Aβ), further inducing Tau phosphorylation and neurotoxicity, and exacerbating the development and progression of Alzheimer's disease. These findings are expected to open a new path for the prevention and treatment of Alzheimer's disease.
Paper link: https://www.nature.com/articles/s41586-024-07185-7 This article is reprinted with permission from the WeChat public account: biological world (ID: ibioworld), the author's biological world