-
Categories
-
Pharmaceutical Intermediates
-
Active Pharmaceutical Ingredients
-
Food Additives
- Industrial Coatings
- Agrochemicals
- Dyes and Pigments
- Surfactant
- Flavors and Fragrances
- Chemical Reagents
- Catalyst and Auxiliary
- Natural Products
- Inorganic Chemistry
-
Organic Chemistry
-
Biochemical Engineering
- Analytical Chemistry
-
Cosmetic Ingredient
- Water Treatment Chemical
-
Pharmaceutical Intermediates
Promotion
ECHEMI Mall
Wholesale
Weekly Price
Exhibition
News
-
Trade Service
*For medical professionals only
On September 27, 2022, Donald Weaver, a neurologist at the University of Toronto, published a systematic review in Alzheimer's & Dementia (IF=16.
655), proposing a new model of Alzheimer's disease (AD), AD 2 This model claims to integrate the different pathogenesis of AD, which may cause a new wave
of discussion in the neurological community.
Figure 1: When the study was published in Alzheimer's & Dementia, AD, it has to mention its two key pathological molecules - amyloid β (Aβ) plaque and tau protein,
The exploration of these two key molecules has been practiced almost throughout the history of
AD research.
Unfortunately, treatments targeting these two star molecules have failed
.
This also inevitably makes researchers wonder: After so many years of research, is it wrong from the beginning?
If the Aβ theory is wrong, another explanation
has to be given.
Some scholars have given a variety of theories including immune abnormalities, microglial abnormalities, neurosynaptic abnormalities, mitochondrial diseases, oxidative stress abnormalities, and ion homeostasis imbalances, and we have also tweeted about it before - β-amyloid is the cause or not? There are many major advances in Alzheimer's disease, but these new assumptions and mechanisms are often mutually exclusive and even in conflict
with the Aβ theory.
But the problem is that even if Aβ-targeting therapies do not work well, its status as a characteristic lesion of AD still exists
.
Therefore, Donald Weaver argues that instead of denying Aβ or other mechanisms, it is better to create an AD model
that can integrate different theories into a comprehensive explanation.
Figure 2: Donald Weaver
What is AD2
Despite the blood-brain barrier, the neuroimmune system, with microglia as the cytoskeleton and cytokines as the chemical skeleton, also puts the brain in the "jurisdiction"
of innate and adaptive immunity.
In the AD2 model, AD is considered to be an innate immune disorder involving the brain, involving autoimmunity as well as autoinflammatory mechanisms
.
The AD2 model also treats Aβ as a key molecule, but it no longer exists as an amyloid misfolding hypothesis, but as a peptide that can exert immunomodulatory and antimicrobial effects, and is part of
AD immunopathology.
In summary, Aβ is synthesized and released as an early response immunopeptide during various pathogen/injury-associated molecular model (PAMP-DAMP) immunostimulatory events (e.
g.
, infection, trauma, ischemia, air pollution, depression), and then initiates an innate immune cascade
。 The immunomodulatory properties of Aβ enhance the process of microglial activation and pro-inflammatory cytokine release, ultimately leading to the death
of apoptotic neurons and bystander neurons through nonspecific autoinflammatory processes.
At the same time, the antimicrobial properties of Aβ can trigger false attacks on neurons under sterile conditions, and the necrotic neuronal products produced during the attack will spread to neighboring neurons, triggering the further release of Aβ, causing a vicious cycle
.
Figure 3: AD2 model schematic
What are the core ideas of the AD2 model?
Professor Donald Weaver has conducted a full range of searches in the fields of biophysics, computational modeling, basic neuroscience, pathology and clinical neurology using specialized search tools such as PubMed, Google, Bing, Wolfram-Alpha, as well as USPTO and WIPO.
To the greatest extent possible, the best evidence-based science is used, and a grading system
for the classification of evidence/papers is established.
A total of 283 articles were included in the analysis
.
Professor Donald Weaver makes the following points:
of innate immunity through multiple pathways 。 Multiple factors including infection, trauma, ischemia, pollution, depression, and metabolic syndrome can trigger AMP release through PAMP/DAMP, and these adverse stimuli are also potentially harmful to the brain and can cause an immune response
mediated by Aβ release.
.
AMPs can interact and bind to microorganisms by the coulombic force, where the positively charged fragment of the AMP band can be negatively attracted by the bacterial membrane surface, thereby inserting adjacent hydrophobic regions into the bacterial cell membrane to initiate bacterial lysis
.
However, due to the similarity of the transmembrane potential gradient between neurons and cells and the use of ion channels and electrical impulses to communicate with bacteria, Aβ can attack neurons
indiscriminately.
In addition, since mitochondrial origin is endocytic bacteria, its antibacterial effect can explain the occurrence of mitochondrial diseases in the AD process: in glial cells, Aβ can cause mitochondrial rupture and mtDNA release in a similar way, activate the GAS-STING pathway and activate the NLPR3 inflammasome to trigger inflammation
.
.
In summary, Aβ interacts with the TREM2-GAG-NLRP3 system to produce a pro-inflammatory cascade that ultimately leads to nonspecific bystander cytotoxicity, leading to autoinflammation leading to neuronal death
.
.
Its chronic and progressive long-term immune response is associated
with the antibacterial effect of Aβ.
Damage to the membrane of neurons "killed" by Aβ further releases the GM1-Aβ complex, which induces neighboring neurons to produce/release Aβ
.
Such a vicious cycle transforms AD into a chronic, self-perpetuating process
.
in brain tumor immunotherapy in the past.
In AD, L-tryptophan can also prevent over-inflammatory production through a variety of biochemical mechanisms: there is evidence of a decrease in plasma L-tryptophan levels in AD patients, and acute L-tryptophan depletion in AD patients increases the likelihood of
cognitive dysfunction.
Similarly, L-arginine and its downstream metabolites also have region-specific variations
in alarm concentrations.
In AD mouse models, citrulline supplementation may improve cognition
by altering L-arginine and nitric oxide levels.
In summary, both the L-tryptophan and L-arginine metabolic pathways are fundamental to controlling innate immunity, and the interaction between these two pathways may be central to
the functional reprogramming of immune cells in immune diseases.
Both have been shown to be direct inhibitors of Aβ oligomerization, which can inhibit AD progression
at multiple sites in vivo.
.
What does the introduction of the AD2 model mean?
In addition to explaining the occurrence and development of AD more completely, the AD2 model may also have a positive impact
on the diagnosis and treatment of AD.
In terms of diagnosis, although there are many blood sample-based AD detection options, most focus on protein misfolding
.
Future detection of L-tryptophan or L-arginine metabolites based on serum or cerebrospinal fluid or further improve the sensitivity and specificity of AD detection; In terms of treatment, the AD2 model gives scientists a chance to "start over" and develop new protocols
based on neuroimmunotherapy that differ from protein abnormally folded targets.
From L-tryptophan, L-arginine to cytokines, protein oligomerization, microglial activation, autophagy, to microbiomics.
.
.
More possible targets have already entered the field of view and may indeed be difficult to achieve in the short term, but in the future, personalized combinations of these different targets are expected to provide patients with more treatment options
.
★ Expert comments on
Professor Han Ying Xuanwu Hospital of Capital Medical University
Where can I see more cutting-edge information?
Come to the "Doctor Station" and take a look 👇
At the end of the article, there is a wonderful comment from Professor Han Ying of Xuanwu Hospital of Capital Medical University, which should not be missed
On September 27, 2022, Donald Weaver, a neurologist at the University of Toronto, published a systematic review in Alzheimer's & Dementia (IF=16.
655), proposing a new model of Alzheimer's disease (AD), AD 2 This model claims to integrate the different pathogenesis of AD, which may cause a new wave
of discussion in the neurological community.
Figure 1: When the study was published in Alzheimer's & Dementia, AD, it has to mention its two key pathological molecules - amyloid β (Aβ) plaque and tau protein,
The exploration of these two key molecules has been practiced almost throughout the history of
AD research.
Unfortunately, treatments targeting these two star molecules have failed
.
This also inevitably makes researchers wonder: After so many years of research, is it wrong from the beginning?
If the Aβ theory is wrong, another explanation
has to be given.
Some scholars have given a variety of theories including immune abnormalities, microglial abnormalities, neurosynaptic abnormalities, mitochondrial diseases, oxidative stress abnormalities, and ion homeostasis imbalances, and we have also tweeted about it before - β-amyloid is the cause or not? There are many major advances in Alzheimer's disease, but these new assumptions and mechanisms are often mutually exclusive and even in conflict
with the Aβ theory.
But the problem is that even if Aβ-targeting therapies do not work well, its status as a characteristic lesion of AD still exists
.
Therefore, Donald Weaver argues that instead of denying Aβ or other mechanisms, it is better to create an AD model
that can integrate different theories into a comprehensive explanation.
Figure 2: Donald Weaver
What is AD2
Despite the blood-brain barrier, the neuroimmune system, with microglia as the cytoskeleton and cytokines as the chemical skeleton, also puts the brain in the "jurisdiction"
of innate and adaptive immunity.
In the AD2 model, AD is considered to be an innate immune disorder involving the brain, involving autoimmunity as well as autoinflammatory mechanisms
.
The AD2 model also treats Aβ as a key molecule, but it no longer exists as an amyloid misfolding hypothesis, but as a peptide that can exert immunomodulatory and antimicrobial effects, and is part of
AD immunopathology.
In summary, Aβ is synthesized and released as an early response immunopeptide during various pathogen/injury-associated molecular model (PAMP-DAMP) immunostimulatory events (e.
g.
, infection, trauma, ischemia, air pollution, depression), and then initiates an innate immune cascade
。 The immunomodulatory properties of Aβ enhance the process of microglial activation and pro-inflammatory cytokine release, ultimately leading to the death
of apoptotic neurons and bystander neurons through nonspecific autoinflammatory processes.
At the same time, the antimicrobial properties of Aβ can trigger false attacks on neurons under sterile conditions, and the necrotic neuronal products produced during the attack will spread to neighboring neurons, triggering the further release of Aβ, causing a vicious cycle
.
Figure 3: AD2 model schematic
What are the core ideas of the AD2 model?
Professor Donald Weaver has conducted a full range of searches in the fields of biophysics, computational modeling, basic neuroscience, pathology and clinical neurology using specialized search tools such as PubMed, Google, Bing, Wolfram-Alpha, as well as USPTO and WIPO.
To the greatest extent possible, the best evidence-based science is used, and a grading system
for the classification of evidence/papers is established.
A total of 283 articles were included in the analysis
.
Professor Donald Weaver makes the following points:
01
Aβ is an immunopeptide that has been recognized as an antimicrobial peptides (AMPs) by a large number of studies and data, which have both immunomodulatory and antimicrobial effects, and can act as a modulatorof innate immunity through multiple pathways 。 Multiple factors including infection, trauma, ischemia, pollution, depression, and metabolic syndrome can trigger AMP release through PAMP/DAMP, and these adverse stimuli are also potentially harmful to the brain and can cause an immune response
mediated by Aβ release.
02
The antibacterial effect of Aβ is neurotoxic As mentioned above, Aβ is an AMP.
AMPs can interact and bind to microorganisms by the coulombic force, where the positively charged fragment of the AMP band can be negatively attracted by the bacterial membrane surface, thereby inserting adjacent hydrophobic regions into the bacterial cell membrane to initiate bacterial lysis
.
However, due to the similarity of the transmembrane potential gradient between neurons and cells and the use of ion channels and electrical impulses to communicate with bacteria, Aβ can attack neurons
indiscriminately.
In addition, since mitochondrial origin is endocytic bacteria, its antibacterial effect can explain the occurrence of mitochondrial diseases in the AD process: in glial cells, Aβ can cause mitochondrial rupture and mtDNA release in a similar way, activate the GAS-STING pathway and activate the NLPR3 inflammasome to trigger inflammation
.
03
Immunomodulatory role of Aβ in neurotoxicity Aβ affects cells and humoral fluids in innate immunity, binds to microglia and affects cytokine release: oligosaccharide Aβ binds to small toe cells through TREM2 receptors and/or membrane-associated glycosaminoglycans, interrupts the role of TREM2 in maintaining neuronal integrity, leading to cytokine expression and apoptosis; Oligomeric Aβ can also interact directly with NLRP3, and altered function of the TREM2-GAG–NLRP system promotes persistent microglia-mediated innate immune dysregulation and TLR4 and CD14 co-receptor stimulation, thereby inducing NFκB and TNFα release.
In summary, Aβ interacts with the TREM2-GAG-NLRP3 system to produce a pro-inflammatory cascade that ultimately leads to nonspecific bystander cytotoxicity, leading to autoinflammation leading to neuronal death
.
04
The role of the typical innate immune peptide of AD is a chronic autoimmune disease will be acute, transient, and self-limited, but Aβ is not.
Its chronic and progressive long-term immune response is associated
with the antibacterial effect of Aβ.
Damage to the membrane of neurons "killed" by Aβ further releases the GM1-Aβ complex, which induces neighboring neurons to produce/release Aβ
.
Such a vicious cycle transforms AD into a chronic, self-perpetuating process
.
05
Role of L-tryptophan and L-arginine in the AD2 model L-tryptophan has been recognized as an immunomodulatorin brain tumor immunotherapy in the past.
In AD, L-tryptophan can also prevent over-inflammatory production through a variety of biochemical mechanisms: there is evidence of a decrease in plasma L-tryptophan levels in AD patients, and acute L-tryptophan depletion in AD patients increases the likelihood of
cognitive dysfunction.
Similarly, L-arginine and its downstream metabolites also have region-specific variations
in alarm concentrations.
In AD mouse models, citrulline supplementation may improve cognition
by altering L-arginine and nitric oxide levels.
In summary, both the L-tryptophan and L-arginine metabolic pathways are fundamental to controlling innate immunity, and the interaction between these two pathways may be central to
the functional reprogramming of immune cells in immune diseases.
Both have been shown to be direct inhibitors of Aβ oligomerization, which can inhibit AD progression
at multiple sites in vivo.
06
Aβ's "off-target" non-immune effector Aβ conformation is flexible, and in addition to binding to immune receptors, it can also bind to a series of non-immune receptors, further increasing the complexity of the pathophysiology of AD.
What does the introduction of the AD2 model mean?
In addition to explaining the occurrence and development of AD more completely, the AD2 model may also have a positive impact
on the diagnosis and treatment of AD.
In terms of diagnosis, although there are many blood sample-based AD detection options, most focus on protein misfolding
.
Future detection of L-tryptophan or L-arginine metabolites based on serum or cerebrospinal fluid or further improve the sensitivity and specificity of AD detection; In terms of treatment, the AD2 model gives scientists a chance to "start over" and develop new protocols
based on neuroimmunotherapy that differ from protein abnormally folded targets.
From L-tryptophan, L-arginine to cytokines, protein oligomerization, microglial activation, autophagy, to microbiomics.
.
.
More possible targets have already entered the field of view and may indeed be difficult to achieve in the short term, but in the future, personalized combinations of these different targets are expected to provide patients with more treatment options
.
★ Expert comments on
Professor Han Ying Xuanwu Hospital of Capital Medical University
Alzheimer's disease (AD) is a complex multifactorial disease whose pathogenesis and pathological mechanism have not yet been clearly explained
.
In the course of AD research, the Aβ hypothesis has received the most extensive attention, and a large number of animal models and clinical studies have confirmed that excessive Aβ deposition in the brain is closely
related to the occurrence and development of AD.
At the same time, however, some of the results contradict the Aβ hypothesis, which has been found to not explain all phenomena, such as studies that have found that AD-characteristic neuronal damage
has occurred in the brain before Aβ deposition.
Based on these contradictory results, a series of AD-related theories have also been proposed, such as mitochondrial dysfunction, lysosomal dysfunction, infection, etc
.
In this context, this review provides a new AD molecular model theory, which does not abandon the traditional Aβ theory, but also integrates other possible pathogenesis on this basis, providing a new idea and direction
for AD diagnosis and treatment.
In the future, more animal models and clinical studies are needed to verify and refine
this theory.
Professor Han Ying
- Chief physician and doctoral supervisor of the Department of Neurology, Xuanwu Hospital, Capital Medical University
- Member of the Magnetic Resonance Committee of the Radiology Branch of the Chinese Medical Association
- President of the Beijing Society of Cognitive Neuroscience
- Chairman of the National Clinical Center for Geriatric Diseases - China AD Preclinical Alliance
- Editorial board member and reviewer of many academic journals at home and abroad
- National Nature Review Expert
References:
[1] Weaver DF.
Alzheimer's disease as an innate autoimmune disease(AD2):A new molecular paradigm.
Alzheimers Dement.
2022 Sep 27.
doi:10.
1002/alz.
12789.
Epub ahead of print.
PMID:36165334.
Where can I see more cutting-edge information?
Come to the "Doctor Station" and take a look 👇
