Immune cells in the brain may be making dense-core plaques as a defence against Alzheimer’s Disease.
The build-up of amyloid-beta plaques in the brain of patients with Alzheimer’s disease (AD) is considered a standard feature of the disease. In fact, most therapies are designed to target these plates.
Now, a new study shows that this common understanding about AD may be partially wrong.
Scientists form the Salk Institute in La Jolla, California, USA, found convincing evidence that one common type of amyloid-beta plaque, the so-called dense-core plaques, may have a protective effect against AD. The findings help explain why so many AD therapies have so far failed.
What we know
AD is a neurological condition characterised by memory loss, impairment of thinking, and behavioural changes – symptoms that worsen with age. In Australia up to 459,000 people suffer from dementia, and Alzheimer’s disease accounts for up to 70% of these cases.
At a cellular level, AD is thought to be caused by the abnormal aggregation of amyloid-beta protein between neurons, leading to formation of the typical plaques associated with the disease. Brain regions affected by these plaques experience loss of synapses, neuron malfunction and eventually, neuronal death.
Two main types of plaques have been described in AD: “diffuse” and “dense-core.” Diffuse plaques are loosely organised, a bit like amorphous clouds, whereas dense-core plaques are more compact, a like a circular core, surrounded by a surrounding halo. The accepted view is that both types of plaques form suddenly, due to over production of a precursor molecule called amyloid precursor protein (APP). Then, the role of microglia is to inhibit the formation of these plaques.
However, according to this new study, some of this story is wrong.
What the study found
The key finding is that microglia are not meant to inhibit the formation of dense core plate. Just the opposite: they promote the formation of these plates, which may actually have a protective function against AD.
“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 Prof Greg Lemke, from Salk’s Molecular Neurobiology Laboratory and lead author of the study in a press release.
“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.”
Previous research by Prof Lemke’s team showed that after a brain cell dies, a fatty molecule emerges from within the cell, and acts as a “eat me” signal, which is picked up by microglia. Microglia cells employ two key molecules, TAM receptors and Gas6, to connect and “eat” the dead brain cells.
Now, in their new study, Prof Lemke shows that the amyloid plaques prevalent in AD also have the “eat me” signal of dead brain cells, as well as the Gas6 molecule. Using mouse models, Prof Lemke’s team show that microglia with TAM receptors “eat” amyloid plaques due to the presence of the “eat-me” signal and Gas6. They also show that mice, genetically engineered to lack TAM receptors, microglia are not able to “eat” amyloid plaques.
Furthermore, using live imaging, the team discovered that after the microglia “eats” bits of a diffuse plaque, it transfers the amyloid-beta protein it extracted from the plaque into to a separate region where it is converted into a compact aggregate that is then added to a dense-core plaque. Researches think that this process serves as a beneficial mechanism to convert diffuse into dense-core plaques.
“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.”
Implications for AD treatment
The new findings have major implications for the development of AD treatments and support the idea of approaches that boost the expression of TAM receptors on microglia, to improve the formation of dense-core plaques. The findings also provide a viable explanation of why some clinical trials of AD have failed.
“… 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,” he said.
Instead of trying to break up dense-core plaques, AD treatments should focus on reducing the production of amyloid-beta or facilitating the transport of this protein out of the brain, Prof Lemke said in the press release.
In the short term, Prof Lemke plans to conduct cognitive studies testing if increasing the activity of microglial TAM receptors leads to a reduction in the symptoms of AD.