Dense-core amyloid plaques may be protective, not destructive, in Alzheimer’s disease

Reuters Health - 03/05/2021 - One type of amyloid plaque, called "dense core" because of its compact center, likely results from the brain's efforts to protect neurons in Alzheimer's disease (AD), studies in mice show.

"A key conclusion from our paper is that AD therapies directed only toward breaking up dense-core amyloid plaques are likely to fail," Dr. Greg Lemke of the Salk Institute for Biological Studies in La Jolla told Reuters Health by email.

As reported in Nature Immunology, Dr. Lemke and colleagues demonstrated in animal models that rather than trying to inhibit the growth of these plaques in the brain, microglia actually promote their formation in an effort to sweep bits of plaque away from neurons.

The findings suggest that dense-core plaques play a protective role, and that treatments aimed at destroying them may do more harm than good, according to the researchers.

Using live imaging, the team found that microglia with TAM receptors - which express the Axl and Mer proteins - phagocytose amyloid plaques, and transfer the engulfed amyloid beta to an acidic compartment, where it is converted into a compacted aggregate that is then transferred to a dense-core plaque.

Notably, in mice engineered to lack TAM receptors (and thus, their proteins), microglia were unable to detect, respond to, organize or phagocytose the plaques. Further, these TAM-deficient mice developed fewer dense-core plaques than Alzheimer mouse models with normal microglia.

The authors state, "Our findings reveal that the TAM system is an essential mediator of microglial recognition and engulfment of amyloid plaques and that TAM-driven microglial phagocytosis does not inhibit, but rather promotes, dense-core plaque development."

Dr. Lemke noted that rather than broadly targeting amyloid plaques, "alternative treatments that should be considered are drugs that might boost Mer expression and phagocytic function in microglia (new PPAR agonists are candidates); or reduce expression of APP - the transmembrane protein whose amino terminus is cleaved to produce the amyloid-beta peptides; or potentiate Mer function in vascular endothelial cells, which also express TAM receptor tyrosine kinases."

Dr. Howard Feldman, Director, Alzheimer's Disease Cooperative Study and Dean, Alzheimer's Disease and Neurodegenerative Research at the University of California, San Diego, called the study "very interesting" and told Reuters Health, "The presence of dense core plaques can be thought of as a marker of a fundamental pathological process in Alzheimer's disease but reflecting the end of the line of amyloid activity, where the host brain is trying to protect itself by rendering the amyloid inert through the formation of dense core plaques."

"However, it does not change the treatment goal of keeping the brain free of amyloid to prevent disease propagation," he said by email. "Removing plaques still holds potential to change the equilibrium of soluble to insoluble amyloid to benefit the host. More reduction of amyloid accumulation could tip the balance from soluble to insoluble forms as well, by removing the triggering effect of soluble amyloid species on tau and other pathophysiological events."

"We are actively learning about the effects of removing amyloid from the brain, including this very end stage of pathology of dense core plaques," he said. "An example of the active interplay between soluble and insoluble forms of amyloid is found in the recent publication on donanemab. Its recent trial (https://bit.ly/3vErKNX) provides evidence that a treatment which reduces both soluble species of amyloid (p-glu species) as well as insoluble aggregated plaques (reduced aggregated plaques on PET) is associated with significant clinical benefits."

SOURCE: https://go.nature.com/3gTlRIC Nature Immunology, online April 15, 2021.

By Marilynn Larkin



Posted on 3 May, 20214 May, 2021