The brain's own "clean up command": Alzheimer's researchers say that some plagues are beneficial

A study reveals that there are crucial differences in the protein deposits in the brain that are typical of Alzheimer's disease. According to this, the diffuse accumulations of amyloid beta protein are more deadly to brain cells than plaques with a dense, compact core.

A key feature of Alzheimer's disease is the accumulation of insoluble clumps of misfolded amyloid beta proteins in the brain. According to current theory, these plaques impede brain metabolism and promote the death of neurons. That is why the plaques are seen as a promising starting point for therapies against progressive brain atrophy. So far, however, tests of such anti-plaque agents have often produced disappointing results .

 

 

Alzheimer's: Difference Between Diffuse and Dense Plaques

A possible explanation for this could now have been found by a team led by Youtong Huang from the Salk Institute for Biological Studies in California. Because not all amyloid plaques are created equal. One variant resembles diffuse clouds of loosely tangled amyloid protein threads. The second plaque variant, on the other hand, is much more compact and consists of a dense core with a looser shell. Up until now it was thought that both forms of plaque develop by themselves and then develop their harmful effects.

But in experiments with mice, the research team has now found that this is not the case. The diffuse plaques do indeed form spontaneously from the precursor proteins - but this does not apply to the denser variant. "We were able to show that the plaques with a dense core do not arise spontaneously. Instead, they are formed by the microglia cells as a protective measure - these plaques should therefore be left alone," reports senior author Greg Lemke from the Salk Institute.

 

 

Compacted by cleanup cells

Specifically, the experiments showed that the denser plaques arise as part of the brain's own "clean-up program". The microglia - a kind of auxiliary cells of the brain - react to certain signal proteins of the neurons: If these are damaged or dead, they carry the so-called TAM receptor on their surface. With the help of another molecule, gas6, the microglia then bind to the dead cell and devour it - this is how damage and waste are disposed of.

As Haung and his colleagues found out, these signaling molecules are also found on the amyloid accumulations typical of Alzheimer's - and the microglia react to them. They engulf the diffuse plaques and convert them into the more compact aggregates. In tests, these dense-core plaques were found to be less damaging to cells than their diffuse precursors, the researchers report.

 

 

Diffuse plaques are more harmful

"If there are more diffuse plaques, then dystrophic neurites - nerve cell extensions that indicate neuronal damage," explains Huang. "The dense plaques, on the other hand, seem to be less harmful: if there are fewer of them, the cell damage is more likely to increase." Apparently, the condensation of the plaques by the microglia helps to gather together the more damaging diffuse amyloid threads, thereby limiting the damage they cause.

"The dense-core plaques could represent an encapsulation mechanism - perhaps analogous to the granulomas in tuberculosis and other infections," the team writes. In these diseases, too, the immune system tries to enclose harmful pathogens and their products in a kind of cyst and thus isolate them. "This compaction, mediated by immune cells, could also limit the spread of toxic amyloid beta oligomers in the brain," said Huang and his colleagues.

 

 

 

Prevent plaques instead of destroying them

This could also explain why some therapeutics tested against Alzheimer's are ineffective: If they primarily attack and remove the dense amyloid plaques, they counteract the clean-up work of the microglia. The agents thus hinder the brain's own protective mechanisms against dementia. "There are various antibodies in approval tests, the main effect of which is to reduce the dense amyloid plaques," says Lemke. "But according to our knowledge, breaking up these deposits could only do more damage."

In the opinion of the scientists, future therapies should therefore focus less on destroying existing plaques. Instead, they think it makes more sense to prevent the formation of the insoluble amyloid beta proteins or to stimulate their natural disposal.

 

 

 

Approaches to new therapies

The signal molecules TAM and Gas6 could offer starting points for this: In the tests, mice with a deficiency in these signal proteins showed a significantly lower activity of the waste disposal microglia. As a result, the particularly harmful diffuse amyloid deposits in particular accumulated in their brains, as the researchers report.

If one now uses active ingredients that upregulate the expression of TAM and Gas6, then this could at least reduce part of the amyloid harmful effect. The first studies on this are already being planned. (Nature Immunology, 2021; doi: 10.1038 / s41590-021-00913-5)

Source: Salk Institute for Biological Studies

This article was written by Nadja Podbregar