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*For medical professional knowledge only for reference, the formation of dense plaques mediated by microglia may be a protective mechanism of the body.
Alzheimer's disease (AD), also known as Alzheimer's disease, is a kind of insidious onset The progressive development of neurodegenerative diseases of the nervous system, the clinical features include cognitive impairment (memory impairment is mostly the first symptom), decreased ability of daily living and abnormal mental behavior.
It is the fourth leading cause of death in the elderly after tumors, heart and cerebrovascular diseases.
The accumulation of beta amyloid into plaques between cells is considered a typical pathological feature of AD.
In addition, Aβ plaques can be divided into diffuse plaques and dense plaques.
Diffuse plaques are loosely organized amorphous clouds.
The ultrastructure shows that dense plaques are composed of a dense core and smaller Aβ fibers (like a halo).
At present, the exact pathogenesis of AD is still unclear.
Among them, the β-amyloid cascade hypothesis has a wider impact.
Why do AD patients suffer from cognitive dysfunction? This hypothesis believes that Aβ deposition in the brain is the central link of AD pathological changes, which can trigger a series of pathological processes, which further promote Aβ deposition, thereby forming a cascade amplification reaction.
Aβ is a normal product in the brain.
It is formed by hydrolysis of amyloid precursor protein by β-secretase and γ-secretase.
There are mainly three types: Aβ1-40, Aβ1-42 and Aβ1-43.
Aβ42/43 is β-sheet Structure, strong hydrophobicity, easy to deposit, and neurotoxic.
There is only a small amount of Aβ42/43 under normal circumstances.
In AD patients, increased Aβ42/43 can cause the following pathological changes: a.
It deposits in the brain to form the core of senile plaques, which can activate microglia and trigger an inflammatory response; b.
It can damage mitochondria and cause energy metabolism disorders and oxygen.
Excessive generation of free radicals leads to oxidative stress damage; c.
It can activate the apoptotic pathway and mediate cell apoptosis; d.
It can also promote the abnormal phosphorylation of tau protein by activating protein kinases; e.
Aβ can also damage bile Alkalinergic neurons cause the pathological changes of the acetylcholine system.
These pathological changes in turn promote the increased production and abnormal deposition of Aβ, resulting in a positive feedback cascade amplification effect, and ultimately lead to clinical cognitive dysfunction.
It is the first proof that microglia with TAM receptors can mediate the formation of dense plaques.
Recently, a scientific research team from the Salk Institute published a paper in Nature Immunology, a sub-publish of Nature [1], on amyloid The "toxicity" of protein plaques raises a new point of view.
Figure 1: Screenshot of the cover of the paper.
They found that through the mediation of TAM receptors, microglia phagocytosed and diffused Aβ to form compact plaques, which were converted into compact aggregates and then discharged to form compact plaques (Figure 2) .
The formation of dense plaques can limit the spread of toxic plaque precursors-Aβ oligomers throughout the brain.
In this way, microglia can clear the debris between cells as a benign compensation for neuroinflammation and neurodegeneration.
Figure 2: TAM (Mer) signal transduction can promote the accumulation of dense Aβ plaques and produce functional consequences to subvert cognition: some dense plaques may be protective! In addition, this study also refutes the traditional view that microglia can swallow Aβ and clear plaques.
On the contrary, microglia actually promote the formation of dense plaques, which is a protective mechanism of the body.
On the one hand, this study may partially explain the failure of phase 3 clinical trials of AD treatment drugs for Aβ plaques (which can break down dense plaques without changing the production of Aβ polypeptides), such as Aducanumab and Crenezumab.
According to reports in the literature, the failure rate of such drugs is as high as 99.
6%, but this does not mean that β-amyloid is harmless.
The author of the article, Professor Lemke, also said in the interview: “Some people have put forward the argument that beta amyloid is harmful to the brain because of the relative failure of clinical trials to eliminate plaque.
But we argue that beta amyloid is still harmful.
However, it is necessary to distinguish whether dense plaques are harmful.
"On the other hand, the study may also partially explain the clinical pathological Aβ deposition and the severity of clinical symptoms are not completely consistent.
Aβ plaques can appear in individuals with normal cognitive function, and nearly 40% of non-demented elderly people can reach the neuropathological standard of AD.
In other words, while detecting plaques in the future, a more detailed distinction should be made between diffuse and dense plaques.
Enlightenment In short, diffuse plaques may be more harmful than dense plaques.
When the body tends to convert diffuse plaques into dense plaques, the damage to the body is relatively reduced.
Based on this discovery, the research team proposed a new direction for the treatment of Alzheimer's disease, such as increasing the expression of TAM receptors on microglia, thereby accelerating the conversion of diffuse Aβ into dense plaques by microglia.
the process of.
In addition, this further suggests that we should inhibit the production of Aβ at the source, and focus on drug development to inhibit the formation of Aβ in the early stage of the disease, rather than removing it after plaque formation.
References: [1]Youtong Huang, Kaisa E.
Happonen, Patrick G.
Burrola, Carolyn O'Connor, Nasun Hah, Ling Huang, Axel Nimmerjahn, Greg Lemke.
Microglia use TAM receptors to detect and engulf amyloid β plaques.
Nature Immunology , 2021; DOI: 10.
1038/s41590-021-00913-5
Alzheimer's disease (AD), also known as Alzheimer's disease, is a kind of insidious onset The progressive development of neurodegenerative diseases of the nervous system, the clinical features include cognitive impairment (memory impairment is mostly the first symptom), decreased ability of daily living and abnormal mental behavior.
It is the fourth leading cause of death in the elderly after tumors, heart and cerebrovascular diseases.
The accumulation of beta amyloid into plaques between cells is considered a typical pathological feature of AD.
In addition, Aβ plaques can be divided into diffuse plaques and dense plaques.
Diffuse plaques are loosely organized amorphous clouds.
The ultrastructure shows that dense plaques are composed of a dense core and smaller Aβ fibers (like a halo).
At present, the exact pathogenesis of AD is still unclear.
Among them, the β-amyloid cascade hypothesis has a wider impact.
Why do AD patients suffer from cognitive dysfunction? This hypothesis believes that Aβ deposition in the brain is the central link of AD pathological changes, which can trigger a series of pathological processes, which further promote Aβ deposition, thereby forming a cascade amplification reaction.
Aβ is a normal product in the brain.
It is formed by hydrolysis of amyloid precursor protein by β-secretase and γ-secretase.
There are mainly three types: Aβ1-40, Aβ1-42 and Aβ1-43.
Aβ42/43 is β-sheet Structure, strong hydrophobicity, easy to deposit, and neurotoxic.
There is only a small amount of Aβ42/43 under normal circumstances.
In AD patients, increased Aβ42/43 can cause the following pathological changes: a.
It deposits in the brain to form the core of senile plaques, which can activate microglia and trigger an inflammatory response; b.
It can damage mitochondria and cause energy metabolism disorders and oxygen.
Excessive generation of free radicals leads to oxidative stress damage; c.
It can activate the apoptotic pathway and mediate cell apoptosis; d.
It can also promote the abnormal phosphorylation of tau protein by activating protein kinases; e.
Aβ can also damage bile Alkalinergic neurons cause the pathological changes of the acetylcholine system.
These pathological changes in turn promote the increased production and abnormal deposition of Aβ, resulting in a positive feedback cascade amplification effect, and ultimately lead to clinical cognitive dysfunction.
It is the first proof that microglia with TAM receptors can mediate the formation of dense plaques.
Recently, a scientific research team from the Salk Institute published a paper in Nature Immunology, a sub-publish of Nature [1], on amyloid The "toxicity" of protein plaques raises a new point of view.
Figure 1: Screenshot of the cover of the paper.
They found that through the mediation of TAM receptors, microglia phagocytosed and diffused Aβ to form compact plaques, which were converted into compact aggregates and then discharged to form compact plaques (Figure 2) .
The formation of dense plaques can limit the spread of toxic plaque precursors-Aβ oligomers throughout the brain.
In this way, microglia can clear the debris between cells as a benign compensation for neuroinflammation and neurodegeneration.
Figure 2: TAM (Mer) signal transduction can promote the accumulation of dense Aβ plaques and produce functional consequences to subvert cognition: some dense plaques may be protective! In addition, this study also refutes the traditional view that microglia can swallow Aβ and clear plaques.
On the contrary, microglia actually promote the formation of dense plaques, which is a protective mechanism of the body.
On the one hand, this study may partially explain the failure of phase 3 clinical trials of AD treatment drugs for Aβ plaques (which can break down dense plaques without changing the production of Aβ polypeptides), such as Aducanumab and Crenezumab.
According to reports in the literature, the failure rate of such drugs is as high as 99.
6%, but this does not mean that β-amyloid is harmless.
The author of the article, Professor Lemke, also said in the interview: “Some people have put forward the argument that beta amyloid is harmful to the brain because of the relative failure of clinical trials to eliminate plaque.
But we argue that beta amyloid is still harmful.
However, it is necessary to distinguish whether dense plaques are harmful.
"On the other hand, the study may also partially explain the clinical pathological Aβ deposition and the severity of clinical symptoms are not completely consistent.
Aβ plaques can appear in individuals with normal cognitive function, and nearly 40% of non-demented elderly people can reach the neuropathological standard of AD.
In other words, while detecting plaques in the future, a more detailed distinction should be made between diffuse and dense plaques.
Enlightenment In short, diffuse plaques may be more harmful than dense plaques.
When the body tends to convert diffuse plaques into dense plaques, the damage to the body is relatively reduced.
Based on this discovery, the research team proposed a new direction for the treatment of Alzheimer's disease, such as increasing the expression of TAM receptors on microglia, thereby accelerating the conversion of diffuse Aβ into dense plaques by microglia.
the process of.
In addition, this further suggests that we should inhibit the production of Aβ at the source, and focus on drug development to inhibit the formation of Aβ in the early stage of the disease, rather than removing it after plaque formation.
References: [1]Youtong Huang, Kaisa E.
Happonen, Patrick G.
Burrola, Carolyn O'Connor, Nasun Hah, Ling Huang, Axel Nimmerjahn, Greg Lemke.
Microglia use TAM receptors to detect and engulf amyloid β plaques.
Nature Immunology , 2021; DOI: 10.
1038/s41590-021-00913-5
