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One of the hallmarks of Alzheimer's disease (AD) is the accumulation of amyloid beta plaques in the brain.
Most therapies aimed at treating AD target these plaques, but most of them have failed in clinical trials.
The new research by Salk scientists overturns the traditional view of the origin of a common plaque, which shows the reason for the failure of the treatment.
The traditional view is that the brain's immune cells called "microglia" that clean up garbage can inhibit the growth of plaques.
Instead, Salk scientists showed that microglia promote the formation of dense plaques, and this action removes the delicate plaque material from neurons, leading to cell death.
This study was published in Nature Immunology on April 15, 2021.
The study showed that dense plaques play a protective role, so the treatment of plaque removal does more harm than good.
DOI: 10.
1038/s41590-021-00913-5 Salk Molecular Neurobiology Laboratory Professor Greg Lemke said that the study proved that dense plaques are not formed spontaneously.
The research team believes that they are constructed by microglia, which is a defense mechanism, and destroying plaques may cause greater damage, so it is best to let them go.
Alzheimer's disease is a neurological disease that causes memory loss, thinking disorders, and behavior changes, which worsen with age.
The disease appears to be caused by the accumulation of abnormal proteins between brain cells to form hallmark plaques that interrupt the activity that keeps the cells alive.
There are many types of plaques, but the two most common plaques are characterized by "diffuseness" and "denseness.
"
Diffuse plaques are amorphous clouds of loose tissue.
The center of the dense patch is tightly surrounded by a halo.
Scientists generally believe that both types of plaques are spontaneously formed by over-produced amyloid precursor protein (APP) precursor molecules.
However, according to this new study, it is actually microglia that form dense plaques from diffuse amyloid beta fibrils as part of their cell clearance.
Lemke's laboratory determined that when brain cells die, fat molecules will transfer from the inside of the cell to the outside, sending a signal: "I'm dead, eat me.
" Microglia pass through surface proteins called TAM receptors, and then use An intermediate molecule called Gas6 swallows or "phagops up" dead cells.
Without TAM receptors and Gas6, microglia cannot connect to dead cells and consume them.
The team’s current work shows that it is not only apoptotic cells that express "can be swallowed" signals and Gas6 amyloid plaques that are prevalent in Alzheimer's disease.
Using an animal model, researchers were able to experimentally prove for the first time that microglia with TAM receptors ingest amyloid plaques through eat-me signaling and Gas6.
In mice designed to lack TAM receptors, microglia cannot perform this function.
APP / PS1Axl -/- Mertk -/- Microglia do not respond to Aβ plaques.
They dig deeper and use real-time imaging to track dense nuclear plaques.
To their surprise, the research team found that after the microglia swallowed the diffuse plaque, the engulfed amyloid β was transferred to the highly acidic compartment, and converted into highly dense aggregates, and then transferred To dense patches.
The researchers proposed that this is a beneficial mechanism that can organize diffusion into dense plaques and clear the debris environment between cells.
The research seems to indicate that when there are fewer dense plaques, there seems to be more harmful effects.
The spread of plaque is greater, and there are a large number of dystrophic neurites, which are representative of neuronal damage.
Researchers believe that there is no clear clinical decision as to which plaque is more or less harmful, but through this study, it seems that dense plaques are more beneficial.
Their findings suggest the development of new methods for the treatment of Alzheimer's disease, such as enhancing the expression of TAM receptors on microglia, thereby accelerating the formation of dense plaques.
The team hopes to conduct cognitive research to understand whether increasing the activity of microglial TAM receptors will reduce the effects of AD.
TAM (Mer) signaling can promote the accumulation of dense Aβ plaques and produce functional consequences.
Lemke is chairman of Françoise Gilot-Salk.
He believes that the current failure rate of most Alzheimer's drug trials is coming to an end.
Lemke said: "Some people say that the relative failure of experiments to destroy dense plaques refutes the idea that amyloid-beta is a bad thing in the brain.
" Lemke suggests, scientists looking for treatments for Alzheimer's disease You should stop trying to focus on breaking down dense core plaques and start looking for treatments that can reduce the production of amyloid-β in the first place, or that can promote the complete transport of amyloid-β out of the brain.
Written | Edited by Sunny | Jessica authorized to reprint and break the news, please contact Metz Medical Administrator MedSci (WeChat ID: medsci_m)
Most therapies aimed at treating AD target these plaques, but most of them have failed in clinical trials.
The new research by Salk scientists overturns the traditional view of the origin of a common plaque, which shows the reason for the failure of the treatment.
The traditional view is that the brain's immune cells called "microglia" that clean up garbage can inhibit the growth of plaques.
Instead, Salk scientists showed that microglia promote the formation of dense plaques, and this action removes the delicate plaque material from neurons, leading to cell death.
This study was published in Nature Immunology on April 15, 2021.
The study showed that dense plaques play a protective role, so the treatment of plaque removal does more harm than good.
DOI: 10.
1038/s41590-021-00913-5 Salk Molecular Neurobiology Laboratory Professor Greg Lemke said that the study proved that dense plaques are not formed spontaneously.
The research team believes that they are constructed by microglia, which is a defense mechanism, and destroying plaques may cause greater damage, so it is best to let them go.
Alzheimer's disease is a neurological disease that causes memory loss, thinking disorders, and behavior changes, which worsen with age.
The disease appears to be caused by the accumulation of abnormal proteins between brain cells to form hallmark plaques that interrupt the activity that keeps the cells alive.
There are many types of plaques, but the two most common plaques are characterized by "diffuseness" and "denseness.
"
Diffuse plaques are amorphous clouds of loose tissue.
The center of the dense patch is tightly surrounded by a halo.
Scientists generally believe that both types of plaques are spontaneously formed by over-produced amyloid precursor protein (APP) precursor molecules.
However, according to this new study, it is actually microglia that form dense plaques from diffuse amyloid beta fibrils as part of their cell clearance.
Lemke's laboratory determined that when brain cells die, fat molecules will transfer from the inside of the cell to the outside, sending a signal: "I'm dead, eat me.
" Microglia pass through surface proteins called TAM receptors, and then use An intermediate molecule called Gas6 swallows or "phagops up" dead cells.
Without TAM receptors and Gas6, microglia cannot connect to dead cells and consume them.
The team’s current work shows that it is not only apoptotic cells that express "can be swallowed" signals and Gas6 amyloid plaques that are prevalent in Alzheimer's disease.
Using an animal model, researchers were able to experimentally prove for the first time that microglia with TAM receptors ingest amyloid plaques through eat-me signaling and Gas6.
In mice designed to lack TAM receptors, microglia cannot perform this function.
APP / PS1Axl -/- Mertk -/- Microglia do not respond to Aβ plaques.
They dig deeper and use real-time imaging to track dense nuclear plaques.
To their surprise, the research team found that after the microglia swallowed the diffuse plaque, the engulfed amyloid β was transferred to the highly acidic compartment, and converted into highly dense aggregates, and then transferred To dense patches.
The researchers proposed that this is a beneficial mechanism that can organize diffusion into dense plaques and clear the debris environment between cells.
The research seems to indicate that when there are fewer dense plaques, there seems to be more harmful effects.
The spread of plaque is greater, and there are a large number of dystrophic neurites, which are representative of neuronal damage.
Researchers believe that there is no clear clinical decision as to which plaque is more or less harmful, but through this study, it seems that dense plaques are more beneficial.
Their findings suggest the development of new methods for the treatment of Alzheimer's disease, such as enhancing the expression of TAM receptors on microglia, thereby accelerating the formation of dense plaques.
The team hopes to conduct cognitive research to understand whether increasing the activity of microglial TAM receptors will reduce the effects of AD.
TAM (Mer) signaling can promote the accumulation of dense Aβ plaques and produce functional consequences.
Lemke is chairman of Françoise Gilot-Salk.
He believes that the current failure rate of most Alzheimer's drug trials is coming to an end.
Lemke said: "Some people say that the relative failure of experiments to destroy dense plaques refutes the idea that amyloid-beta is a bad thing in the brain.
" Lemke suggests, scientists looking for treatments for Alzheimer's disease You should stop trying to focus on breaking down dense core plaques and start looking for treatments that can reduce the production of amyloid-β in the first place, or that can promote the complete transport of amyloid-β out of the brain.
Written | Edited by Sunny | Jessica authorized to reprint and break the news, please contact Metz Medical Administrator MedSci (WeChat ID: medsci_m)