April 27 2023
Posted December 7, 2021
Whenever Aβ plaques are brought up in a discussion about Alzheimer’s Disease (AD), the general sentiment is: Aβ plaques are harmful. But a new study published in Nature Immunology by Greg Lemke, Ph.D. of the Salk Institute, suggests that it’s not quite that simple. In fact, Lemke’s study possibly explains why AD therapeutics that target and break up dense core plaques have resulted in only marginal cognitive benefits.
Dense core plaques are so named because of their compact (and dense) center. They stand in contrast to the wispy, more diffuse Aβ plaques also seen in the brain. Despite their different physical characteristics, scientists have long believed that all Aβ plaques are formed in the same way: spontaneously and in response to the excess production of amyloid precursor protein or APP. However, Lemke’s research counter-intuitively reveals that dense core plaques are no spontaneous accident and suggests that dense core plaques may actually be playing a protective role in the brain.
The story of this unexpected discovery begins with two key microglial receptors previously implicated in AD: Axl and Mer. Microglia can be thought of as the waste-clearing cells of the brain; when wispy Aβ plaques are present, microglia engulf and clear out the waste, preventing the plaques from causing neuronal cell death and controlling the spread of toxic Aβ plaques.
To study the roles of Axl and Mer more closely, Lemke’s team first compared microglia in two different mouse models: one group with functional Axl and Mer receptors and another without. Predictably, in the mice with functional Axl and Mer receptors, microglia were able to normally detect, respond to and engulf Aβ plaques, whereas, in the group lacking the functional receptors, the microglia could not.
At the outset, the researchers expected that mice lacking in Axl and Mer would show more dense-core plaque accumulation since they would be lacking the microglial-mediated Aβ clearance. Surprisingly, they observed the complete opposite result: mice without the functional Axl and Mer receptors had far fewer dense-core plaques in the brain than the mice with functional Axl and Mer receptors.
This result led the researchers to wonder: “How does a tenfold reduction in phagocytic capacity, coupled with a twofold reduction in microglial numbers and a fivefold reduction in plaque binding, result in 35% fewer dense-core plaques?”
Ultimately, the researchers propose a model that incorporates several clues from other research studies. First, previous research has shown that when microglia die, they release any Aβ they’d previously engulfed into the extracellular space, promoting the growth of even more dense core Aβ plaques. Second, the intracellular environment into which Aβ material is typically deposited when engulfed by microglia is highly acidic; these Aβ fibrils in this environment are then compacted into dense-core material and are resistant to breakdown. Finally, in brains treated with drugs that kill microglia, plaques do not appear—suggesting that microglia are actually responsible for the formation of dense-core plaques in the first place.
Perhaps, the researchers speculate, these dense-core plaques are actively built by microglia as a way to protect the brain from the harm that toxic pre-plaque Aβ oligomers would otherwise cause. This possibility would certainly explain why drugs designed to break up dense-core Aβ plaques largely fail to offer significant cognitive benefit. Eliminating the brain’s attempt at defending itself in a bad case scenario is no ideal treatment option.
Importantly, this study does not suggest that Aβ plaques are innocuous (they’re not), but when the brain is faced with increased Aβ deposition, the formation of Aβ dense core plaques may be one way the brain works to minimize harm. If this is the case, future therapies targeting Aβ plaques might be better off leaving those dense core plaques alone.
Greg Lemke, Ph.D., Salk Institute
(Primary Author: Youong Huang)
April 27 2023
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