加州大学旧金山分校的科学家发现，大脑中特定免疫细胞（称为小胶质细胞）能有效消化导致阿尔茨海默病的毒性β淀粉样蛋白斑块。他们确定了一个关键受体ADGRG1，该受体能触发这种保护机制。当小胶质细胞缺乏此受体时，斑块会快速积聚，导致记忆丧失和脑损伤；而存在该受体时，阿尔茨海默病症状可维持在轻微状态。由于ADGRG1属于易被药物作用的受体家族，这一发现为未来开发增强大脑免疫力、保护更多人抵御阿尔茨海默病的疗法开辟了新途径。
In Alzheimer's disease, proteins like amyloid beta form clumps, known as plaques, that damage the brain.
But in some people, immune cells called microglia break down these proteins before they can cause harm. This leads to fewer and smaller clumps -- and much milder symptoms.
Researchers at UC San Francisco identified a molecular receptor that enables microglia to gobble up and digest amyloid beta plaques.
Without the receptor, ADGRG1, the microglia barely nibbled on the toxic protein. Using a mouse model of Alzheimer's disease, the researchers observed how the loss of ADGRG1 led to the rapid buildup of amyloid plaques, neurodegeneration, and problems with learning and memory.
"We think this receptor helps microglia do their job of keeping the brain healthy over many years," said Xianhua Piao, MD, PhD, a physician-scientist in the UCSF Department of Pediatrics.
Indeed, when the researchers reanalyzed a prior study of gene expression in the human brain, they found that individuals who died of mild Alzheimer's had microglia with abundant ADGRG1, and mild cognitive impairment -- implying that the microglia ate well and kept the disease in check. But in those who died of severe Alzheimer's, the microglia had very little ADGRG1, and the plaques proliferated.
ADGRG1 is one of hundreds of G protein-coupled receptors, which are routinely targeted in drug development. This bodes well for a rapid translation of the discovery into new therapies.
"Some people are lucky to have responsible microglia," Piao said. "But this discovery creates an opportunity to develop drugs to make microglia effective against amyloid-beta in everyone."
Authors: Other UCSF authors are Beika Zhu, PhD, Andi Wangzhou, PhD, Diankun Yu, PhD, Tao Li, PhD, Rachael Schmidt, Stacy L. De Florencio, Lauren Chao, RN, Alicia L. Thurber, Minqi Zhou, Zeina Msheik, PhD, Yonatan Perez, PhD, Lea T. Grinberg, MD, PhD, Salvatore Spina, MD, PhD, Richard M. Ransohoff, MD, Arnold R. Kriegstein, MD, PhD, William W. Seeley, MD, and Tomasz Nowakowski, PhD.
Funding: This work was funded in part by the National Institutes of Health (P01AG019724, P50AG023501, R01NS094164, R01NS108446, K99AG081694), the Consortium for Frontotemporal Dementia Research, the Tau Consortium, the Alzheimer's Association (23AARG-NTF-1030341), the Cure Alzheimer's Fund, and the BrightFocus foundation postdoctoral fellowship (A2021020F).