EMBO J: Zhiyuan Zhang/Zhiren Zhang's team discovered the importance of a new mechanism of systematic Aβ clearance for Alzheimer's disease

Professor Zhang Zhiyuan's research group from the School of Basic Medical Sciences of Nanjing Medical University and Professor Zhang Zhiren's research group from the All-Army Institute of Immunology of Army Medical University published a research paper
in EMBO Journal entitled "Erythropoietin signaling in peripheral macrophages is required for systemic β-amyloid clearance.
"

This study revealed the mechanism by which erythropoietin(EPO) signaling mediates systemic β-amyloid (Aβ) clearance in peripheral macrophages and its significance and role
in the pathogenesis and progression of Alzheimer's disease (AD).

Clearing neurotoxic β-amyloid (Aβ) in the brain has been the mainstay strategy
for the mitigation and treatment of Alzheimer's disease (AD).
However, the intervention method of direct central Aβ clearance has many adverse reactions and inconveniences
.
Professor Zhang Zhiyuan's research group has tried to promote central Aβ outflow by peripheral Aβ clearance, thereby indirectly reducing Aβ deposition in the brain and improving related neuropathological changes and cognitive function
.
This study discovered the mechanism that regulates the clearance of Aβ by peripheral macrophages, thus providing new ideas
for the effective treatment of AD.

Several recent GWAS studies in patients with sporadic AD have highlighted the association of immune cell abnormalities with the onset of AD, but previous studies of Aβ clearance by monocytic macrophage systems have focused on infiltration and invasion of a small number of cells into the brain, while the associated role of more peripheral macrophages remains unknown
.
At the same time, the previous research of the research group showed that EPO receptors can inhibit the expression of inflammatory genes in macrophages and promote their phagocytosis
.

On this basis, the paper further found that EPO can promote macrophage phagocytosis degradation of Aβ by agonizing PPARγ, and inhibit the inflammatory response
caused by Aβ.
Conditional knockout of peripheral macrophage EPO receptor increased peripheral and central Aβ levels, which in turn aggravated the pathological damage and cognitive and behavioral deficits
associated with AD model mice.

Moreover, the study found that the EPOR signaling pathway of peripheral macrophages of aged AD mice was significantly downregulated compared with young AD model mice.
Exogenous EPO can reverse the EPOR signaling defect of peripheral macrophages in aging AD mice, improve macrophage phagocytosis and slow down the pathological process
of AD.
At the same time, this study verified an EPO analogue without redness-promoting side effects, which greatly improved the druggability and clinical application of this mechanism
.

This study proposes that peripheral clearance of Aβ can help reduce the level of Aβ in the brain and slow down AD-related neuropathological changes, and also has a clearer understanding of the specific mechanism of peripheral macrophages involved in systemic Aβ clearance and its association with the pathogenesis and pathological progression of AD, which provides a new strategy
for the research of new drugs for the treatment of AD.

Xu Lu, a lecturer from the Department of Pathology, School of Basic Medical Sciences, Nanjing Medical University, and Li Lei, a master's student, are the co-first authors of the paper, and Professor Zhang Zhiyuan of Nanjing Medical University and Professor Zhang Zhiren of Army Medical University are co-corresponding authors
.
Hu Fan, State Key Laboratory of Reproduction, Nanjing Medical University, provided important support
for this study.
The research was supported
by the National Natural Science Foundation of China and the Jiangsu Province Innovation and Innovation Team.