One of the characteristic hallmarks of Alzheimer's disease (AD) is the
buildup of amyloid-beta plaques in the brain. Most therapies designed to
treat AD target these plaques, but they've largely failed in clinical
trials. New research by Salk scientists upends conventional views of the
origin of one prevalent type of plaque, indicating a reason why treatments
have been unsuccessful.
The traditional view holds that the brain's trash-clearing immune cells,
called microglia, inhibit the growth of plaques by "eating" them. The Salk
scientists show instead that microglia promote the formation of dense-core
plaques, and that this action sweeps wispy plaque material away from
neurons, where it causes cell death. The research, which was published in
Nature Immunology on April 15, 2021, suggests that dense-core plaques play a
protective role, so treatments to destroy them may do more harm than good.
"We show that dense-core plaques don't form spontaneously. We believe
they're built by microglia as a defense mechanism, so they may be best left
alone," says Greg Lemke, a professor in Salk's Molecular Neurobiology
Laboratory. "There are various efforts to get the FDA to approve antibodies
whose main clinical effect is reducing dense-core plaque formation, but we
make the argument that breaking up the plaque may be doing more damage."
Alzheimer's disease is a neurological condition that results in memory loss,
impairment of thinking, and behavioral changes, which worsen as we age. The
disease seems to be caused by abnormal proteins aggregating between brain
cells to form the hallmark plaques, which interrupt activity that keeps the
cells alive.
There are numerous forms of plaque, but the two most prevalent are
characterized as "diffuse" and "dense-core." Diffuse plaques are loosely
organized, amorphous clouds. Dense-core plaques have a compact center
surrounded by a halo. Scientists have generally believed that both types of
plaque form spontaneously from excess production of a precursor molecule
called amyloid precursor protein (APP).
But, according to the new study, it is actually microglia that form
dense-core plaques from diffuse amyloid-beta fibrils, as part of their
cellular cleanup.
This builds on a 2016 discovery by the Lemke lab, which determined that when
a brain cell dies, a fatty molecule flips from the inside to the outside of
the cell, signaling, "I'm dead, eat me." Microglia, via surface proteins
called TAM receptors, then engulf, or "eat" the dead cell, with the help of
an intermediary molecule called Gas6. Without TAM receptors and Gas6,
microglia cannot connect to dead cells and consume them.
The team's current work shows that it's not only dead cells that exhibit the
eat-me signal and Gas6: So do the amyloid plaques prevalent in Alzheimer's
disease. Using animal models, the researchers were able to demonstrate
experimentally for the first time that microglia with TAM receptors eat
amyloid plaques via the eat-me signal and Gas6. In mice engineered to lack
TAM receptors, the microglia were unable to perform this function.
Digging deeper, they traced the dense-core plaques using live imaging. Much
to their surprise, the team discovered that after a microglial cell eats a
diffuse plaque, it transfers the engulfed amyloid-beta to a highly acidic
compartment and converts it into a highly compacted aggregate that is then
transferred to a dense-core plaque. The researchers propose that this is a
beneficial mechanism, organizing diffuse into dense-core plaque and clearing
the intercellular environment of debris.
"Our research seems to show that when there are fewer dense-core plaques,
there seem to be more detrimental effects," says Youtong Huang, first author
on the paper. "With more-diffuse plaques, there's an abundance of dystrophic
neurites, a proxy for neuronal damage. I don't think there's a distinct
clinical decision on which form of plaque is more or less detrimental, but
through our research, we seem to find that dense-core plaques are a bit more
benign."
Their findings suggest new ways of developing a treatment for Alzheimer's
disease, such as boosting expression of TAM receptors on microglia to
accelerate dense-core plaque formation. The team would like to conduct
cognitive studies to see if increasing the activity of microglial TAM
receptors would alleviate the effects of AD.
Lemke, who holds the Françoise Gilot-Salk Chair, believes that the current
failure rate of most Alzheimer's drug trials is about to end. "Some people
are saying that the relative failure of trials that bust up dense-core
plaques refutes the idea that amyloid-beta is a bad thing in the brain,"
says Lemke. "But we argue that amyloid-beta is still clearly a bad thing;
it's just that you've got to ask whether dense-core plaques are a bad
thing."
Lemke suggests that scientists looking for a cure for Alzheimer's should
stop trying to focus on breaking up dense-core plaques and start looking at
treatments that either reduce the production of amyloid-beta in the first
place or therapies that facilitate transport of amyloid-beta out of the
brain altogether.
Reference:
Huang Y, Happonen KE, Burrola PG, et al. Microglia use TAM receptors to
detect and engulf amyloid β plaques. Nat Immunol. 2021:1-9. doi:
10.1038/s41590-021-00913-5
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Medical Science