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▎Editor of WuXi AppTec's content team recently, researchers from Harvard Medical School and Massachusetts General Hospital (MGH) published a study on Alzheimer's disease in Cell Reports under "Cell" , Uncovered the mystery that has plagued for many years: how the key protein that affects Alzheimer's disease-amyloid beta (Aβ, amyloid beta) is formed in the axons of brain neurons and structures related to neural connections of.
Researchers have found that by blocking a key protein called the "sigma-1 receptor (S1R)", the formation of beta amyloid can be reduced.
Researchers are expected to develop new treatments for Alzheimer's disease based on this result to slow the progression and onset of this disease.
The corresponding author of this study is Professor Rudolph Tanzi, a well-known neurogeneticist.
In 1986, his research team discovered an Alzheimer's disease gene, called the "APP gene", which directs the production of APP (amyloid precursor protein).
When APP protein is cleaved by β-secretase and γ-secretase, the by-product is β-amyloid protein.
▲Professor Rudolph Tanzi shared his insights on developing treatments for Alzheimer's disease at WuXi AppTec Global Forum.
Related reading: Fighting aging and neurological diseases: just a short shot? | WuXi AppTec Global Forum records that the symptoms of Alzheimer's disease patients are related to the dysfunction and death of brain nerve cells.
Neuron axons and their peripheral structures are the most severely damaged parts of Alzheimer's disease.
The massive deposition of beta amyloid is considered to be an important cause of Alzheimer's disease.
Because this toxic protein is formed in the axons and nerve endings of nerve cells in the brain, it will trigger a series of chain reactions, including hindering the transport function of nerve cell axons, leading to neuroinflammation and the death of nerve cells.
"We know that beta amyloid is formed in the axons of nerve cells in the brain, but we don't know how it is formed.
" Professor Tanzi explained.
In order to answer this question, the research team conducted several years of experiments to study the brains of mice, and established a tool to study AD using a three-dimensional cell culture model in a petri dish.
Image source: 123RF As early as 2013, scientists discovered that APP protein first undergoes a process called palmitoylation (palmitoylation) to form palAPP, and then produce beta amyloid.
They also found that in neurons, palAPP is transported through fatty vesicles called "lipid rafts.
"
The newly published study shows that a special lipid raft called "mitochondrial-associated endoplasmic reticulum membranes (MAMs)" in neurons is the place where APP protein is processed by β-secretase and makes β-amyloid protein.
The process only occurs when beta amyloid damages axons.
The researchers pointed out that although previous studies have shown that the number and activity of MAM in the brains of Alzheimer's patients have increased, this is the first time scientists have learned that MAM is also a "manufacturing workshop" for beta amyloid.
▲Activating the S1R protein can up-regulate the formation of β-amyloid in MAM, and vice versa (picture source: reference [1]) Based on this discovery, researchers have tried to reduce the number or activity of MAM through gene therapy or drugs.
They found that blocking the key protein S1R can prevent MAM assembly, significantly reduce the β-secretase cleavage of palAPP in axons, and then reduce the production of β-amyloid.
Conversely, a drug that activates the S1R protein can trigger an increase in the β-secretase cleavage of palAPP and the production of β-amyloid in axons.
Professor Tanzi said: "Our research results indicate that S1R may be a viable therapeutic target for specifically reducing the production of amyloid β in axons.
" According to the press release of the research institution, the lead author of this article, Dora M.
Kovacs The doctor is studying whether another type of ACAT inhibitor that can directly act on MAM can be used to prevent β-amyloid formation.
Researchers hope that in the future, interventions that block the production of beta amyloid in axons can be used in conjunction with early detection (through blood or imaging tests) to prevent or slow the progression of Alzheimer's disease.
Related reading: With just one simple step, you can quickly clear the "garbage" in your brain! "Nature" hot discussion: The root cause of Alzheimer's disease is.
.
.
microbial infection? Fighting aging and neurological diseases: just one step away? | WuXi AppTec Global Forum Record Reference: [1] Bhattacharyya, R.
, et, al.
(2021).
Axonal generation of amyloid-β from palmitoylated APP in mitochondria-associated endoplasmic reticulum membranes.
Cell Reports, 35(7) , 109134.
https://doi.
org/10.
1016/j.
celrep.
2021.
109134[2] Getting to the Root of Alzheimer's.
Retrieved May 19, 2021, from https://hms.
harvard.
edu/news/getting-root -alzheimers[3] Study solves mystery of how amyloid beta, a key player in Alzheimer's, forms in brain nerve cells.
Retrieved May 19, 2021, from https:// solves-mystery-of-how-amyloid-beta-a-key-player-in-Alzheimers-form-%20in-brain-nerve-cells
Researchers have found that by blocking a key protein called the "sigma-1 receptor (S1R)", the formation of beta amyloid can be reduced.
Researchers are expected to develop new treatments for Alzheimer's disease based on this result to slow the progression and onset of this disease.
The corresponding author of this study is Professor Rudolph Tanzi, a well-known neurogeneticist.
In 1986, his research team discovered an Alzheimer's disease gene, called the "APP gene", which directs the production of APP (amyloid precursor protein).
When APP protein is cleaved by β-secretase and γ-secretase, the by-product is β-amyloid protein.
▲Professor Rudolph Tanzi shared his insights on developing treatments for Alzheimer's disease at WuXi AppTec Global Forum.
Related reading: Fighting aging and neurological diseases: just a short shot? | WuXi AppTec Global Forum records that the symptoms of Alzheimer's disease patients are related to the dysfunction and death of brain nerve cells.
Neuron axons and their peripheral structures are the most severely damaged parts of Alzheimer's disease.
The massive deposition of beta amyloid is considered to be an important cause of Alzheimer's disease.
Because this toxic protein is formed in the axons and nerve endings of nerve cells in the brain, it will trigger a series of chain reactions, including hindering the transport function of nerve cell axons, leading to neuroinflammation and the death of nerve cells.
"We know that beta amyloid is formed in the axons of nerve cells in the brain, but we don't know how it is formed.
" Professor Tanzi explained.
In order to answer this question, the research team conducted several years of experiments to study the brains of mice, and established a tool to study AD using a three-dimensional cell culture model in a petri dish.
Image source: 123RF As early as 2013, scientists discovered that APP protein first undergoes a process called palmitoylation (palmitoylation) to form palAPP, and then produce beta amyloid.
They also found that in neurons, palAPP is transported through fatty vesicles called "lipid rafts.
"
The newly published study shows that a special lipid raft called "mitochondrial-associated endoplasmic reticulum membranes (MAMs)" in neurons is the place where APP protein is processed by β-secretase and makes β-amyloid protein.
The process only occurs when beta amyloid damages axons.
The researchers pointed out that although previous studies have shown that the number and activity of MAM in the brains of Alzheimer's patients have increased, this is the first time scientists have learned that MAM is also a "manufacturing workshop" for beta amyloid.
▲Activating the S1R protein can up-regulate the formation of β-amyloid in MAM, and vice versa (picture source: reference [1]) Based on this discovery, researchers have tried to reduce the number or activity of MAM through gene therapy or drugs.
They found that blocking the key protein S1R can prevent MAM assembly, significantly reduce the β-secretase cleavage of palAPP in axons, and then reduce the production of β-amyloid.
Conversely, a drug that activates the S1R protein can trigger an increase in the β-secretase cleavage of palAPP and the production of β-amyloid in axons.
Professor Tanzi said: "Our research results indicate that S1R may be a viable therapeutic target for specifically reducing the production of amyloid β in axons.
" According to the press release of the research institution, the lead author of this article, Dora M.
Kovacs The doctor is studying whether another type of ACAT inhibitor that can directly act on MAM can be used to prevent β-amyloid formation.
Researchers hope that in the future, interventions that block the production of beta amyloid in axons can be used in conjunction with early detection (through blood or imaging tests) to prevent or slow the progression of Alzheimer's disease.
Related reading: With just one simple step, you can quickly clear the "garbage" in your brain! "Nature" hot discussion: The root cause of Alzheimer's disease is.
.
.
microbial infection? Fighting aging and neurological diseases: just one step away? | WuXi AppTec Global Forum Record Reference: [1] Bhattacharyya, R.
, et, al.
(2021).
Axonal generation of amyloid-β from palmitoylated APP in mitochondria-associated endoplasmic reticulum membranes.
Cell Reports, 35(7) , 109134.
https://doi.
org/10.
1016/j.
celrep.
2021.
109134[2] Getting to the Root of Alzheimer's.
Retrieved May 19, 2021, from https://hms.
harvard.
edu/news/getting-root -alzheimers[3] Study solves mystery of how amyloid beta, a key player in Alzheimer's, forms in brain nerve cells.
Retrieved May 19, 2021, from https:// solves-mystery-of-how-amyloid-beta-a-key-player-in-Alzheimers-form-%20in-brain-nerve-cells
