Novel Antibody-Based Therapy Shows It Could Be A Viable Mode of Treatment for Alzheimer's Disease

Researchers led by Professor Zhiqiang An, Ph.D. from McGovern Medical School at the University of Texas Health Science Center, and Professor Ningyan Zhang, Ph.D. from the Texas Therapeutics Institute at the Brown Foundation Institute of Molecular Medicine report that a newly developed agnostic antibody has therapeutic effects on the mice with Alzheimer's disease.

The antibody-based therapy is said to have reduced the amyloid pathology in the mice in the experiment, signaling a promise of a potential treatment for the disease. Researchers published the findings of their study, titled "A tetravalent TREM2 agonistic antibody reduced amyloid pathology in a mouse model of Alzheimer's disease," in Science Translational Medicine.

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Novel Antibody-Based Therapy Shows It Could Be A Viable Mode of Treatment for Alzheimer's Disease

Antibody Triggers Activation of TREM2

Alzheimer's disease is the most common type of dementia that is characterized by the loss of memory and thinking skills, which affects over 10% of the elderly. The disease is due to the amyloid-beta oligomers and plaques in the brain's parenchyma.

Researchers found that a tetra-variable domain antibody that targets the triggering receptor expressed on myeloid 2 (TREM2) reduced the amyloid burden, eased brain damage, and alleviated cognitive decline in mice with Alzheimer's disease, Genetic Engineering & Biotechnology News reported.

TREM2 is a receptor in microglia, which plays a crucial role in amyloid-beta pathology. TREM2 is responsible for the regulation of the migration of microglia toward the phagocytosis of amyloid-beta oligomers and plaques that leads to Alzheimer's disease. The research postulates that increasing TREM 2 activation would enhance those effects.

But an engineered antibody could accomplish this and presents a potential treatment for the disease. They wrote that panning a phage-displayed single-chain variable fragment Ab library enabled them to discover TREM2 agonist monoclonal Ab (Ab18).

"By engineering the bivalent immunoglobulin G1 (IgG1) to tetra-variable domain immunoglobulin (TVD-Ig), we further increased the TREM2 activation by 100-fold," researchers wrote. Then they further enhanced its potency to enter the brain by more than tenfold.

They found that the antibody has positive effects on the mice model of Alzheimer's disease. Each week, the mice would show a considerable reduction of amyloid burden with increased microglia migration, the improved intensity of neurons and synapses, improved cognitive functions, and other marks.

Researchers concluded that the antibody-based TREM2-targeting therapies are a potential treatment for Alzheimer's disease, although more work is needed to support and confirm the results. Zhang noted that the findings show that antibody engineering results in developing effective TREM2-targeting therapies for the disease.

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The Link Between TREM2 and Dementia

According to a paper in Frontiers, scientists found that the brain immune cells microglia play a proactive role in the pathogenesis of Alzheimer's Disease after discovering the associated variants of the disease in the TREM2 gene.

This gene is only expressed in immune cells of myeloid origin and is involved in many aspects of myeloid cell function and interaction with other cell types. The complexity of its functions is found in cell or tissue content-dependent responses to stimuli of different natures and timing.

For example, isolated TREM2-deficient cells increased the production of pro-inflammatory molecules in vitro. On the other hand, intact tissues demonstrated that the pro- and anti-inflammatory roles of TREM2 in brain immunity depend on the timing after stimulation, genetic background, and stage of pathology.

The TREM2's selective expression on immune cells and its association with different forms of dementia imply its contribution to the common pathways of neurodegenerative diseases.