Is Alzheimer's disease a brain disease? Toronto General Hospital proposed a new hypothesis

There have been many opinions about the pathogenesis of Alzheimer's disease, and the "β amyloid" hypothesis, which attracted the most attention, fell off the altar
in Science's falsification of the 2006 paper that provided key evidence.
This paper proposes a new hypothesis
of the pathogenesis of Alzheimer's disease from the perspective of autoimmune diseases.
Alzheimer's disease (AD), commonly known as Alzheimer's disease, patients with progressive memory and cognitive decline, personality and behavior will change, gradually lose the ability to live, late often due to infectious complications of death
.
The incidence of the elderly over 65 years old in Europe and the United States is 5%, and the incidence of the elderly over 85 years old reaches more than
30%.
According to the 2017 National Epidemiological Survey of Mental Diseases, the prevalence rate of people over 65 years old in China is 5.
56%.

So far, however, there have been no therapies to prevent, stop, or treat AD
.
As Chinese society gradually enters the aging stage and the elderly population continues to rise, AD will become more and more common, bringing a huge burden
to family members and society.

Among the many theories that explain the cause of AD, the "β amyloid" hypothesis can be said to be unique, attracting countless researchers to devote themselves to related research
.
The hypothesis holds that amyloid precursor protein shear forms β amyloid (amyloid-β, Aβ), Aβ aggregates to form oligomers, and dissolvency deteriorates into brown plaques, resulting in neurofibrillary tangles, neuronal loss, etc
.
Aβ was identified in 1984 as the main component
of plaque in the brains of people with dementia.
In 2006, a key paper published in the journal Nature provided strong evidence for the hypothesis and inspired future generations to work
this path.

However, the controversy over this hypothesis has never stopped, especially when people find that clinical treatment options based on this hypothesis have failed, which shakes confidence in
this hypothesis 。 In 2020, a study published in Neurology, "Objective subtle cognitive difficulties predict future amyloid accumulation and neurodegeneration," proposed that neurodegenerative lesions with subtle cognitive difficulties appear before large deposition of Aβ, which may not be the cause of the disease, but the result of disease development
。 A 2021 study published in EclinicalMedicine, "High cerebrospinal amyloid-β 42 is associated with normal cognition in individuals with brain amyloidosis," proposed that the consumption of highly soluble Aβ peptide 42 led to the occurrence
of cognitive impairment 。 In June 2022, Nature Neuroscience published another study titled "Faulty autolysosome acidification in Alzheimer's disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques", It is proposed that the death of nerve cells begins with autophagy lysosomal dysfunction, and the appearance of extracellular amyloid plaques is later than cell death, and even the "wreckage" of the cell is mixed
with Aβ.

But what really dealt a fatal blow to the "β amyloid" hypothesis was the anti-counterfeiting campaign
from Science two months ago 。 The town-circle paper, "A specific amyloid-β protein assembly in the brain impairs memory," which has been cited by scholars worldwide about 2,300 times in the 16 years since its publication, has been pointed out for academic misconduct (Figure 1), and the authenticity of more than 70 images in the paper has undoubtedly triggered a tsunami
in the AD research community 。 Figure 1 Nature suggests that the paper is under investigation (Source: Nature) But scientific research has never been a smooth road, a high-rise building has collapsed, and there must be countless latecomers rising from the rubble
.
The research team from Toronto General Hospital has put forward a new idea referred to as AD² through extensive review of the previous literature, arguing that AD is not a disease of the brain, but a chronic autoimmune disease of the
brain.
The findings were published on September^{27, 2022} under the title "Alzheimer's disease as an innate autoimmune disease (AD 2): A new molecular paradigm" (Figure 2).

Figure 2 Research results (Source: [1]) AD^2's view is that in order to deal with various pathogen-associated molecular patterns (PAMPS, such as infection, air pollution) and damage-associated molecular patterns (DAMPs, such as trauma, ischemia, depression, Obesity) immune stimulation event, Aβ as an early immune peptide is synthesized and released, triggering innate immune cascade reaction, Aβ's immunomodulatory properties enhance the sustained activation of microglia and the continuous release of pro-inflammatory cytokines, resulting in non-specific autoinflammation, resulting in the death of apoptotic neurons, and in the process, bystander neurons are also killed
.
AD² still considers Aβ to be an important player in the model, but unlike the "β amyloid" hypothesis, AD² treats Aβ as an immunopeptide that volatilizes immunomodulatory and antimicrobial effects, and is only part of a complex and vast system under the framework of
AD immunopathology.

Figure 3 The main points of the AD² model (Source: [1]) are as follows:

1

Aβ is an immune peptide with a large amount of data supporting the identification of Aβ as antimicrobial peptides (AMPs, also known as host defense peptides), and Aβ meets the classification criteria for
cytokines.
AMPs and cytokines are essential intrinsic peptides in the brain that have both antibacterial and immunomodulatory functions, with oligomerization or aggregation being part of their normal function, rather than pathological processes
.
The same is true
for Aβ.

2

The antibacterial effect of Aβ has the neurotoxicity of AMP combined with invading microorganisms through coulomb force, while the transmembrane potential of bacteria and the use of ion channels and electrical impulses to communicate are similar
to neurons.
This results in Aβ also attacking neurons
.
The amyloidosis metabolic pathway produces the more neurotoxic Aβ1-42
.
The antimicrobial effect of Aβ also incorporates the effects of mitochondrial lesions and metal balance disorders into the
AD² model.

3

Immunomodulatory role of Aβ in neurotoxicity Aβ interacts with the immunomodulatory interaction of the TREM2–GAG–NLRP3 system, producing a pro-inflammatory cascade, and excessive activation of pro-inflammatory microglial activity leads to non-specific bystander cytotoxicity
.
Since synaptic membranes are similar to bacteria and are more susceptible to direct attack by Aβ/AMP, the synaptic toxicity exhibited by AD becomes understandable
.
At the same time, the action of Aβ and TREM2–GAG–NLRP3 systems inhibits the promotion of TREM2, GAG and NLRP3 receptors on normal synaptic function, plasticity and elasticity processes, resulting in abnormal synaptic pruning and additional synaptic loss
.

4

AD is a chronic autoimmune disease Aβ immune response chronic from the antibacterial effect of Aβ, necrotic neurons in the subsequent breakdown products include the release of monosialic acid tetrahexosylganglioside (GM1)-Aβ molecular complex, which spreads to nearby neurons, triggering further release of Aβ, resulting in chronic, self-sustained autoimmune circulation
.
In addition, the patient's blood-brain barrier is eventually destroyed, and macrophages from outside the brain will further exacerbate disease development
.

5

The immune processes of L-tryptophan and L-arginine are strictly regulated by homeostasis, and both innate immunity and adaptive immunity have endogenous control systems
.
Past studies have described L-tryptophan and L-arginine as "controllers" of innate immunity, L-tryptophan and L-arginine have been shown to be direct inhibitors of Aβ oligomerization, and decreased L-tryptophan levels are associated with increased cognitive dysfunction or more readily available AD, and altering L-arginine and nitric oxide levels in mouse models improves cognitive decline
.

6

The "off-target" non-immune effects of Aβ, like other cytokines and immune peptides, are flexible in conformation and bind not only to immune receptors, but also to a range of non-immune receptors
.
This receptor-binding heterogeneity of Aβ increases the diversity of AD pathology and the complexity
of its multiple immunopathological mechanisms.

The AD² model not only explains the initiation and progression of AD-related disease processes, but also provides candidate general targets (autoimmunity) and specific targets (L-tryptophan metabolism, L-arginine metabolism) for future development of diagnostics and treatment options, such as diagnosis by measuring L-tryptophan or L-arginine metabolite levels in the patient's serum or cerebrospinal fluid, or designing combination therapies to counter the pathogenesis of multiple and cross-disturbing between AD.
Adapting and reusing known drugs is also worth considering
.

Figure 4 Repurposing known drugs (Source: [1])

Given the complexity of AD, the AD² model still has some limitations, such as difficulty responding to clinical heterogeneity between patients with AD and between early-onset and late-onset diseases, and does not explain well the decades-long interval
between the occurrence of neurochemical changes and the first onset of symptoms.
But the AD² model proposes a broadly inclusive framework that unifies many different theories into a comprehensive explanation, suggesting that the final treatment may require rational multipartisanship rather than a "magic bullet.
"

Author of the article| Wind Standing Night

Typography | Kiko Ku

End

Resources:

[1] Donald F.
Weaver.
Alzheimer's disease as an innate autoimmune disease (AD²): A new molecular paradigm.
Alzheimer's & Dementia, 2022; DOI: 10.
1002/alz.
12789