Targeting Alzheimer’s with a soluble toll-like receptor

3D brain against purple background
Scientists found that soluble TLR5 can reduce the buildup of amyloid plaques in mouse models of Alzheimer's disease. (alex-mit/iStock/Getty Images Plus)

Alzheimer’s disease is characterized by the toxic accumulation of beta-amyloid and the brain’s immune response, which backfires to cause neuro-inflammation. Scientists at the University of Florida found that soluble versions of toll-like receptors (TLR)—proteins believed to play a key role in the neuro-inflammatory response seen in Alzheimer's—could hold promise in reversing amyloid plaques.

In Alzheimer’s disease, TLRs represent a double-edged sword. Some of them first play a protective role by helping to clear beta-amyloid. As the disease progresses, however, their prolonged response to neuronal damage could induce inflammation and lead to further neurodegeneration.

The Florida researchers, led by Paramita Chakrabarty and Todd Golde, noticed that Alzheimer’s patients have more TLRs in their brains than do people without the disease. TLRs reside in the brain on the surface of immune cells called microglia. They are known to participate in microglia-mediated immune response that recognize molecules released by pathogens or damaged cells.

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Could freeing some TLRs from microglia reduce the formation of amyloid plaques? The researchers tested that hypothesis in a mouse model of Alzheimer’s. In mice that expressed large amounts of human beta-amyloid, they found that soluble TLR5 prevented and even reversed the amyloid plaque buildup. They published their findings in the Journal of Experimental Medicine.

Charkrabarty and colleagues figured soluble TLR5 act as “decoy receptors” that bind to beta-amyloid and enhance their uptake into microglia without activating cellular signaling pathways that would lead to inflammation. They also observed that beta-amyloid lost some of its ability to kill cultured neurons.

RELATED: Gradually eliminating BACE1 clears amyloid plaque from mice with Alzheimer’s

Scientists have suggested that TLRs and microglia could become potential targets to treat Alzheimer’s. For example, a study in the journal Brain, Behavior, and Immunity in 2016 showed that an anti-TLR2 antibody reduced amyloid plaques in mouse models of Alzheimer's and decreased microglial activation. A study published at about the same time in the Journal of Immunology found that stimulating TLR4 could help reduce Tau proteins, which have also been implicated in the disease, and improve cognitive function in mice.

That said, several clinical flops in Alzheimer's research have cast doubts on the amyloid hypothesis. Merck & Co. recently racked up a failure for its candidate targeting BACE, which is involved in the formation of beta-amyloid plaques, while Janssen terminated its BACE inhibitor based on safety concern. Even a rare win touted by Biogen and Eisai for their antibody BAN2401 in its ability to clear amyloid was seen by many as weak.

The University of Florida researchers now believe that soluble TLR5 could be a novel class of immunotherapy for Alzheimer’s. But Charkrabarty acknowledged that the mouse model they used in the study does not represent the entire Alzheimer’s neurodegenerative cascade. “Therefore, the potential of soluble TLR5 in dampening immune activation and related neurotoxic pathways needs to be further explored in multiple models of Alzheimer's disease,” she said in a statement.