Novel agonist antibody reduces amyloid pathology in mice with Alzheimer’s disease

A newly developed agonist antibody reduced amyloid pathology in mice with Alzheimer’s disease, signaling its promise as a potential treatment for the disease, according to a team of researchers at UTHealth Houston.

Research led by lead author Zhiqiang An, PhD, Professor and Robert A. Welch Distinguished University Chair in Chemistry at McGovern Medical School at UTHealth Houston, found that a tetra-variable domain antibody targeting the myeloid-expressed trigger receptor 2 (TREM2) – dubbed TREM2 TVD-lg – reduced amyloid load, attenuated neuron damage, and attenuated cognitive decline in mice with Alzheimer’s disease. The study was published today in Science Translational Medicine.

Antibody therapy is a viable drug modality for the treatment of Alzheimer’s disease. One of the Texas Therapeutics Institute’s primary areas of interest is developing technologies to deliver antibody-based therapies across the blood-brain barrier for potential treatment of disease.”

Zhiqiang An, director of the Texas Therapeutics Institute with the Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM)

TREM2 is a single-pass receptor expressed by microglia – support cells that function as scavengers in the central nervous system. Microglia play a crucial role in clearing amyloids that cluster around amyloid-beta plaques, a hallmark of Alzheimer’s disease.

While previous research has shown that TREM2 plays an important role in the pathophysiology of Alzheimer’s disease, recent findings suggest that increasing TREM2 activation may have therapeutic effects such as improved cognition .

“By leveraging the unique antibody drug discovery capabilities at UTHealth Houston and collaborating with scientists with complementary expertise, we have demonstrated the feasibility of designing multivalent TREM2 agonist antibodies coupled with TfR-mediated brain delivery to improve functions. microglia and reduce amyloid pathology in vitro and in vivo,” said co-lead author Ningyan Zhang, PhD, professor at IMM’s Texas Therapeutics Institute at McGovern Medical School. “This antibody engineering approach enables the development of effective therapies targeting TREM2 for AD.”

Other UTHealth Houston IMM authors include Peng Zhao, PhD, postdoctoral researcher; Yuanzhong Xu, PhD, assistant professor; Xuejun Fan, MD, PhD, research scientist; Leike Li, PhD, postdoctoral researcher; Xin Li, associate researcher; and Qingchun Tong, PhD, Cullen Professor and Chair in Molecular Medicine. Wei Cao, PhD, Roy M. and Phyllis Gough Huffington Professor Emeritus of Anesthesiology at McGovern Medical School, also contributed to the study. An, Tong and Cao are also faculty members at the University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences.

Other co-authors include LuLin Jiang, PhD, of Sanford Burnham Prebys Medical Discovery Institute in California; Hisashi Arase, MD, of Osaka University in Japan; Hui Zheng, PhD, with Baylor College of Medicine in Houston; Yingjun Zhao, PhD, with Xiamen University in China; and Huaxi Xu, PhD, with Xiamen University and Chongqing Medical University in China.

The work was partially supported by grants from the Cancer Prevention and Research Institute of Texas (RP150551 and RP190561) and the Welch Foundation.


University of Texas Health Sciences Center at Houston

Journal reference:

Zhao, P. et al. (2022) A tetravalent TREM2 agonist antibody reduced amyloid pathology in a mouse model of Alzheimer’s disease. Science Translational Medicine.

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