Improving Blood Monocyte Energy Metabolism Enhances Its Ability to Phagocytose Amyloid-β and Prevents Alzheimer’s Disease-Type Pathology and Cognitive Deficits
Zhi‑Hao Liu1,2,3 · Yu‑Di Bai2,3 · Zhong‑Yuan Yu2,3 · Hui‑Yun Li2,3 · Jie Liu2,3 · Cheng‑Rong Tan2,3 · Gui‑Hua Zeng2,3 · Yun‑Feng Tu2,3 · Pu‑Yang Sun2,3 · Yu‑Juan Jia2,3 · Jin‑Cai He1 · Yan‑Jiang Wang1,2,3,4,5,6 · Xian‑Le Bu2,3,4,51 Department of Neurology, The First Afliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
2 Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing 400042, China
3 Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing 400042, China
4 Institute of Brain and Intelligence, Third Military Medical University, Chongqing 400042, China
5 State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing 400042, China
6 Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 201200, China
Abstract
Deficiencies in the clearance of peripheral amyloid β (Aβ) play a crucial role in the progression of Alzheimer’s disease (AD). Previous studies have shown that the ability of blood monocytes to phagocytose Aβ is decreased in AD. However, the exact mechanism of Aβ clearance dysfunction in AD monocytes remains unclear. In the present study, we found that blood monocytes in AD mice exhibited decreases in energy metabolism, which was accompanied by cellular senescence, a senescence-associated secretory phenotype, and dysfunctional phagocytosis of Aβ. Improving energy metabolism rejuvenated monocytes and enhanced their ability to phagocytose Aβ in vivo and in vitro. Moreover, enhancing blood monocyte Aβ phagocytosis by improving energy metabolism alleviated brain Aβ deposition and neuroinflammation and eventually improved cognitive function in AD mice. This study reveals a new mechanism of impaired Aβ phagocytosis in monocytes and provides evidence that restoring their energy metabolism may be a novel therapeutic strategy for AD.
Keywords
Alzheimer’s disease; Aβ clearance; Monocyte; Phagocytosis; Energy metabolism
