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Alzheimer's disease (AD), commonly known as Alzheimer's disease, has a great impact on
the health and quality of life of the elderly in China.
Wang Haidong, director of the Department of Aging of the National Health Commission, said that there are about 15 million dementia patients in the elderly aged 60 and above in China, of which 10 million are Alzheimer's disease patients
.
In order to solve the mystery of Alzheimer's disease, scientists have long focused on studying protein misfolding and aggregation, such as β amyloid plates and tau protein tangles
.
However, anti-amyloid or anti-protein misfolding drugs do not hold great promise
for disease treatment.
In addition, the amyloid hypothesis β has also been controversial
in recent years.
Dr.
Donald F.
Weaver, director of the Krembil Brain Institute at the University of Toronto, Canada, synthesized journal literature and patents in clinical neuroscience, systems biology, neurobiology, immunology, biochemistry, and drug design to propose the "AD squared" model (AD^ 2）
。 The results, titled "Alzheimer's disease as an innate autoimmune disease (AD^2): A new molecular paradigm," were recently published in
the journal Alzheimer's & Dementia.
What is the "AD squared" model?
Dr.
Weaver believes that in response to physiological immune stimuli (such as infection, trauma, ischemia, air pollution, depression, etc.
), the body synthesizes β amyloid and releases
it as an early-response immunopeptide.
This will trigger an innate immune cascade in which oligomeric β amyloid exerts immunomodulatory and antibacterial roles
.
"AD squared" model diagram
The main content
of the "AD squared" model β amyloid is an immunopeptide antimicrobial peptides (AMPs) and cytokines that are essential innate immune peptides
in the brain.
There is substantial evidence that β amyloid can be used both as an antimicrobial peptide and as a cytokine definition
.
When β amyloid is released, it can play both antibacterial and immunomodulatory roles
.
Even in the absence of microorganisms, β amyloid has antibacterial properties
.
Immunopeptides and cytokines typically have baseline serum levels that increase with age, reflecting their age-dependent physiological role
in innate immunity.
Consistent with this phenomenon, baseline levels of amyloid
β can also be detected in the serum of normal, healthy subjects who did not receive sustained immune stimulation.
β antimicrobial action of amyloid has a positively charged fragment of neurotoxic antimicrobial peptides that attract each other to the surface of the negatively charged bacterial membrane, thereby binding
to invading bacteria through coulombic interactions.
Next, hydrophobic fragments of antimicrobial peptides adjacent to the binding site are inserted into the microbial membrane, causing membrane rupture, which leads to cytoplasmic leakage and cell necrosis
.
Because β amyloid has the characteristics of antimicrobial peptides, and neurons and bacteria have high similarities in transmembrane potential gradients and extramembrane anionic macromolecules, amyloid β will "mistakenly" damage the body's own neurons
.
β amyloid is also involved in two neurochemical reactions: β non-amyloidosis metabolic pathways involving amyloid fragments 1-40; β amyloidosis metabolic pathway
involving amyloid fragments 1-42.
Multiple studies have confirmed that bacterial and viral infections promote β- and γ-secretases, which dominate β amyloid fragments 1-42 and amyloidosis metabolic pathways
.
β amyloid fragments 1-42 have sequence homology to bacteriocins and structural similarities to conserved antimicrobial peptides and viral fusion domains, thus having a stronger antimicrobial effect, but also accompanied by higher neurotoxicity
.
In addition, antimicrobial properties may also explain the role
of mitochondrial lesions and metal homeostasis dysregulation in disease development.
β the immunomodulatory function of amyloid is also neurotoxic β amyloid binds to microglia and affects the release and action of cytokines, thereby resonating the cellular and humoral components
of the brain's innate immunity.
In response to a series of stimuli, β amyloid is released as a molecular trigger that initiates a broad immune cascade
.
β pro-inflammatory cascade resulting from the interaction of amyloid with the immune regulation of the TREM2–GAG–NLRP3 system, forming a nonspecific cytotoxic bystander cytotoxicity, ultimately leading to neuronal death
due to autoinflammation.
Alzheimer's disease is a chronic autoimmune disease β the chronicity of the amyloid immune response comes from the rupture
of neuronal membranes caused by autobacterial effects.
Necrotic neurons release the GM1–Aβ complex, which further induces neighboring healthy neurons to produce or release β amyloid, transforming Alzheimer's into a chronic, self-perpetuating process
.
Some explanation for why Alzheimer's disease occurs later in life, because symptomatic Alzheimer's disease requires the loss of 30 to 45 percent of the 85 billion neurons in the brain, a spontaneous process that takes decades to achieve
.
In addition, due to the disruption of the final blood-brain barrier in elderly patients with dementia, senescent fat cells and liver cells activate macrophages into a pro-inflammatory state, which then enters the central nervous system to further accelerate the deterioration
of the disease.
The function of L-tryptophan and L-arginine is strictly regulated by homeostasis in the immune process, and both innate and adaptive immunity have endogenous control systems, which provide drug targets for immune dysfunction-related diseases
.
L-tryptophan is considered the "key regulator" and control system of innate immunity, while L-arginine acts as the "master and commander"
of innate immunity.
Both the L-tryptophan and L-arginine metabolic pathways underlie innate immune control, and the interaction between these two pathways may be key to
the reprogramming of immune cell function in basic immune diseases.
In addition, both L-tryptophan and L-arginine β direct inhibitors
of amyloid oligomerization.
β amyloid off-target non-immune effector cytokines and related immunopeptides are flexible in conformation, β amyloid is no exception, they can bind
not only to immune receptors, but also to a range of non-immune receptors.
β the heterogeneity of amyloid receptor binding makes the already diverse pathological and immunopathological mechanisms of Alzheimer's disease more complex
.
Changes in the metabolism of L-tryptophan and L-arginine in different regions of the brain of elderly patients with dementia deserve further studyto understand its role in the onset and progression of
the disease.
Although
the "β amyloid" hypothesis has suffered a fatal blow due to the recent paper counterfeiting incident, the "AD squared" model in this paper still believes that amyloid β is an important participant in
Alzheimer's disease.
Dr.
Weaver said in an interview with the media: β Amyloid can't tell the difference between bacteria and brain cells, so it inadvertently attacks our own brain cells
.
" Then, this becomes what we call an autoimmune disease
.
The immune system is actually attacking the host, our own brain
.
The "AD squared" model in this paper, in addition to providing a mechanistic explanation for the occurrence and development of Alzheimer's disease, also finds potential general targets (autoimmunity) and specific targets (L-tryptophan metabolism, L-arginine metabolism)
for the diagnosis and treatment of diseases.
Dr.
Weaver, director of the Klimbir Institute, has been working from home in recent days due to epidemic prevention and control.
This is a rare time after graduating from college to stay with
your family.
Perhaps one day in the future, Alzheimer's disease will also come to their families, hoping that scientists will overcome the disease
as soon as possible.
I wish parents all over the world health and peace
.
The articles reproduced by the "Yaodu" public account are from other official account platforms, and the main purpose is to share industry-related knowledge and transmit the latest current information
.
The copyright of pictures and articles belongs to the original author, if there is any infringement, please inform us in time, and we will delete the relevant information
within 24 hours.
the health and quality of life of the elderly in China.
Wang Haidong, director of the Department of Aging of the National Health Commission, said that there are about 15 million dementia patients in the elderly aged 60 and above in China, of which 10 million are Alzheimer's disease patients
.
In order to solve the mystery of Alzheimer's disease, scientists have long focused on studying protein misfolding and aggregation, such as β amyloid plates and tau protein tangles
.
However, anti-amyloid or anti-protein misfolding drugs do not hold great promise
for disease treatment.
In addition, the amyloid hypothesis β has also been controversial
in recent years.
Dr.
Donald F.
Weaver, director of the Krembil Brain Institute at the University of Toronto, Canada, synthesized journal literature and patents in clinical neuroscience, systems biology, neurobiology, immunology, biochemistry, and drug design to propose the "AD squared" model (AD^ 2）
。 The results, titled "Alzheimer's disease as an innate autoimmune disease (AD^2): A new molecular paradigm," were recently published in
the journal Alzheimer's & Dementia.
What is the "AD squared" model?
Dr.
Weaver believes that in response to physiological immune stimuli (such as infection, trauma, ischemia, air pollution, depression, etc.
), the body synthesizes β amyloid and releases
it as an early-response immunopeptide.
This will trigger an innate immune cascade in which oligomeric β amyloid exerts immunomodulatory and antibacterial roles
.
"AD squared" model diagram
The main content
of the "AD squared" model β amyloid is an immunopeptide antimicrobial peptides (AMPs) and cytokines that are essential innate immune peptides
in the brain.
There is substantial evidence that β amyloid can be used both as an antimicrobial peptide and as a cytokine definition
.
When β amyloid is released, it can play both antibacterial and immunomodulatory roles
.
Even in the absence of microorganisms, β amyloid has antibacterial properties
.
Immunopeptides and cytokines typically have baseline serum levels that increase with age, reflecting their age-dependent physiological role
in innate immunity.
Consistent with this phenomenon, baseline levels of amyloid
β can also be detected in the serum of normal, healthy subjects who did not receive sustained immune stimulation.
β antimicrobial action of amyloid has a positively charged fragment of neurotoxic antimicrobial peptides that attract each other to the surface of the negatively charged bacterial membrane, thereby binding
to invading bacteria through coulombic interactions.
Next, hydrophobic fragments of antimicrobial peptides adjacent to the binding site are inserted into the microbial membrane, causing membrane rupture, which leads to cytoplasmic leakage and cell necrosis
.
Because β amyloid has the characteristics of antimicrobial peptides, and neurons and bacteria have high similarities in transmembrane potential gradients and extramembrane anionic macromolecules, amyloid β will "mistakenly" damage the body's own neurons
.
β amyloid is also involved in two neurochemical reactions: β non-amyloidosis metabolic pathways involving amyloid fragments 1-40; β amyloidosis metabolic pathway
involving amyloid fragments 1-42.
Multiple studies have confirmed that bacterial and viral infections promote β- and γ-secretases, which dominate β amyloid fragments 1-42 and amyloidosis metabolic pathways
.
β amyloid fragments 1-42 have sequence homology to bacteriocins and structural similarities to conserved antimicrobial peptides and viral fusion domains, thus having a stronger antimicrobial effect, but also accompanied by higher neurotoxicity
.
In addition, antimicrobial properties may also explain the role
of mitochondrial lesions and metal homeostasis dysregulation in disease development.
β the immunomodulatory function of amyloid is also neurotoxic β amyloid binds to microglia and affects the release and action of cytokines, thereby resonating the cellular and humoral components
of the brain's innate immunity.
In response to a series of stimuli, β amyloid is released as a molecular trigger that initiates a broad immune cascade
.
β pro-inflammatory cascade resulting from the interaction of amyloid with the immune regulation of the TREM2–GAG–NLRP3 system, forming a nonspecific cytotoxic bystander cytotoxicity, ultimately leading to neuronal death
due to autoinflammation.
Alzheimer's disease is a chronic autoimmune disease β the chronicity of the amyloid immune response comes from the rupture
of neuronal membranes caused by autobacterial effects.
Necrotic neurons release the GM1–Aβ complex, which further induces neighboring healthy neurons to produce or release β amyloid, transforming Alzheimer's into a chronic, self-perpetuating process
.
Some explanation for why Alzheimer's disease occurs later in life, because symptomatic Alzheimer's disease requires the loss of 30 to 45 percent of the 85 billion neurons in the brain, a spontaneous process that takes decades to achieve
.
In addition, due to the disruption of the final blood-brain barrier in elderly patients with dementia, senescent fat cells and liver cells activate macrophages into a pro-inflammatory state, which then enters the central nervous system to further accelerate the deterioration
of the disease.
The function of L-tryptophan and L-arginine is strictly regulated by homeostasis in the immune process, and both innate and adaptive immunity have endogenous control systems, which provide drug targets for immune dysfunction-related diseases
.
L-tryptophan is considered the "key regulator" and control system of innate immunity, while L-arginine acts as the "master and commander"
of innate immunity.
Both the L-tryptophan and L-arginine metabolic pathways underlie innate immune control, and the interaction between these two pathways may be key to
the reprogramming of immune cell function in basic immune diseases.
In addition, both L-tryptophan and L-arginine β direct inhibitors
of amyloid oligomerization.
β amyloid off-target non-immune effector cytokines and related immunopeptides are flexible in conformation, β amyloid is no exception, they can bind
not only to immune receptors, but also to a range of non-immune receptors.
β the heterogeneity of amyloid receptor binding makes the already diverse pathological and immunopathological mechanisms of Alzheimer's disease more complex
.
Changes in the metabolism of L-tryptophan and L-arginine in different regions of the brain of elderly patients with dementia deserve further studyto understand its role in the onset and progression of
the disease.
Although
the "β amyloid" hypothesis has suffered a fatal blow due to the recent paper counterfeiting incident, the "AD squared" model in this paper still believes that amyloid β is an important participant in
Alzheimer's disease.
Dr.
Weaver said in an interview with the media: β Amyloid can't tell the difference between bacteria and brain cells, so it inadvertently attacks our own brain cells
.
" Then, this becomes what we call an autoimmune disease
.
The immune system is actually attacking the host, our own brain
.
The "AD squared" model in this paper, in addition to providing a mechanistic explanation for the occurrence and development of Alzheimer's disease, also finds potential general targets (autoimmunity) and specific targets (L-tryptophan metabolism, L-arginine metabolism)
for the diagnosis and treatment of diseases.
Dr.
Weaver, director of the Klimbir Institute, has been working from home in recent days due to epidemic prevention and control.
This is a rare time after graduating from college to stay with
your family.
Perhaps one day in the future, Alzheimer's disease will also come to their families, hoping that scientists will overcome the disease
as soon as possible.
I wish parents all over the world health and peace
.
Resources:
1.
http://news.
china.
com.
cn/2022-09/20/content_78429230.
html
2.
Weaver DF.
Alzheimer’s disease as an innate autoimmune disease (AD^2): A new molecular paradigm.
Alzheimer’s Dement.
2022; 1-13.
3.
Lesné, S.
, Koh, M.
, Kotilinek, L.
et al.
A specific amyloid-β protein assembly in the brain impairs memory.
Nature 440, 352–357 (2006).
4.
style="margin: 8px;text-align: left;line-height: 1.
5em;">
disclaimer
The articles reproduced by the "Yaodu" public account are from other official account platforms, and the main purpose is to share industry-related knowledge and transmit the latest current information
.
The copyright of pictures and articles belongs to the original author, if there is any infringement, please inform us in time, and we will delete the relevant information
within 24 hours.
