Heavy! Chinese scientists have uncovered the mechanism by which lectins cause Alzheimer's disease

Alzheimer's disease, also known as senile dementia, is a progressive neurodegenerative disease that is the cause
of nearly two-thirds of people with dementia.
The deposition of amyloid β (Aβ) to form nerve plaques (NP) is a hallmark
of Alzheimer's disease (AD).
Major non-genetic risk factors such as aging, stroke, and diabetes promote the onset of AD, but the mechanism is unclear
.
In addition, the mechanism of NP formation is unclear
.


Previous studies have shown that an imbalance of clusterin (CLU) is associated
with the pathogenesis of AD.
CLU is a secretory protein that is synthesized primarily in astrocytes in the brain, and knocking out CLU significantly reduces NP formation, but we still don't know the exact mechanism of
it.

On September 23, 2022, Signal Transduction and Targeted Therapy published a research article "Clusterin transduces Alzheimer-risk signals to amyloidogenesis" jointly communicated by Wang Zhe, Song Weihong and Wu Yili of Capital Medical University.
It is revealed that CLU affects the occurrence/development of Alzheimer's disease by regulating the formation of amyloid protein, providing us with new ideas
for the prevention and treatment of Alzheimer's disease.


Aging is a key risk factor for Alzheimer's disease, and it has been previously found that people with diabetes are more likely to develop Alzheimer's disease, but the mechanism by which these two risk factors contribute to Alzheimer's disease is unclear
.
In recent years, some scholars have found that plasma CLU concentration is related to brain atrophy, disease severity and clinical progress in AD patients, and whether AD risk factors such as aging and diabetes affect the development process of AD through CLU?
The researchers examined the expression of CLU in the brains of wild-type mice at 3 and 18 months through immunofluorescence experiments, and found that at 3 months, CLU was only expressed in brainstem neurons, while in the brains of 18-month mice, CLU was concentrated in large numbers in cortical neurons, and at the same time, by injecting insulin receptor inhibitor S961 to build type 2 diabetes model mice, cortical neurons were also found to express CLU
in large quantities.

In mice in models of aging (a) and type 2 diabetes (b), CLU was clustered in large numbers in

cortical neurons, and what was even more surprising was that in models of stroke (including ischemic stroke and hemorrhagic stroke) and herpes simplex virus (HSV) infection, CLU was significantly elevated in extracellular regions of both neurons and damaged regions, while stroke and HSV infection were also risk factors for AD onset
。
In the brains of model mice with ischemia (MCAO), lactate treatment (simulating an acidic environment of stroke), bleeding, and HSV infection, CLU is upregulated
in neuronal and extracellular regions Under the action of various AD risk factors, CLU has shown an increase in neuronal expression in the brain, so what is the impact of rising CLU expression? The researchers then used the syn-1 promoter to specifically overexpress human CLU (hCLU) in APP/PS1 model mouse neurons, and found that the survival rate of mice was significantly reduced, and the open-field experiment was a classic emotion-related behavioral detection experiment, which showed that hCLU overexpression aggravated the depression/anxiety performance
of APP/PS1 model mice.

(Left) overexpression of hCLU in neurons reduces survival in AD model mice (right) hCLU exacerbates depression/anxiety in AD model mice, manifests extracellular deposits of large amounts of amyloid plaques (also known as nerve plaques
) are one of the most recognized neuropathological features of
AD.
Aβ42 has been shown to be highly hydrophobic and prone to polymerization, and its self-polymerization of oligomers has strong neurotoxicity to AD neurons
.
syn1-hCLU (neuron-specific overexpression of human CLU) can increase amyloid accumulation in the brain of mice, and the area of nerve plaque also increases
.

The syn1-hCLU promotes the formation of amyloid and the
increase of neural plaque area Aβ is mainly produced
by amyloid precursor protein (APP) being β secretase and γ secretase clipping.
APP is a transmembrane glycoprotein widely present in neurons, in which the classic pathway of Aβ production is to produce C99 by β secretase hydrolysis, and then by γ secretase hydrolysis to produce amyloid
.

The production pathway
of amyloid has been previously demonstrated that CLU can promote the formation of amyloid protein, but the molecular mechanism is still unclear, so researchers speculate that CLU can regulate the activity of γ-secretase, thereby affecting the latter's hydrolysis of C99, as expected, GSI (γ-secretase inhibitor) blocks the role of hCLU in promoting the formation of
Aβ.

By mediating the activity of γ-secretase to promote the formation of
Aβ further through IP experiments, the researchers demonstrated that CLU can bind to the near-membrane helix (JH) domain of C99 and competitively inhibit the blocking effect of the JH domain on γ-secretase, thereby activating γ-secretase and achieving hydrolysis
of C99.

CLU and C99's JH domain strongly bind, thereby lifting the inhibition
of γ-secretase AD patients brain nerve cell apoptosis rate is about 40 times higher than normal people, apoptosis neuronal cell remains will become amyloid home, thereby forming nerve plaque, so nerve cell apoptosis may be one of the main causes of
central nervous system decline 。 Through immunofluorescence experiments, the researchers found that neurons that overexpressed hCLU showed a decrease or even complete disappearance of NeuN signal, while the apoptosis signal was significantly enhanced, suggesting that CLU may be involved in the formation
of nerve plaques through apoptosis.

Neurons overexpressing hCLU exhibit increased
apoptosis using DNase-1 to induce apoptosis, and then treat apoptotic cells by Triton X-100, a nonionic surfactant that can disrupt protein-lipid interactions, but does not denature the protein, nor does it destroy the protein-to-protein connection, and can retain the natural conformation
of the protein.
Analysis of protein pellets by mass spectrometry revealed that they contained a large number of nerve plaques, and the content of CLU in them also increased
significantly.

Based on this result, the research team proposed a model of CLU-dependent Aβ deposition on the surface of apoptotic cells, providing a
new way
to explain the mechanism of nerve plaque formation in the brain of AD patients.

Aβ relies on CLU deposition on the surface of apoptotic cells, thereby forming nerve plaquesIn general, this study shows that the main risk factors for AD will upregulate CLU expression, CLU promotes the formation of nerve plaques by binding to the JH domain of C99, activating γ-secretase, and at the same time, due to CLU accumulation in apoptotic cells, Aβ can be deposited on the surface of apoptotic cells through CLU, thereby promoting the formation of nerve plaques

。 This study reveals for the first time the molecular mechanism of CLU promoting amyloid and neural plaque formation, which provides an important reference for clinical treatment of
AD.

Article link: source | Biovalley Editor | Swagpp
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