The Brain-Yi Chenju/Niu Jianqin team found that activating the Wnt/β-catenin pathway relieved blood-brain barrier dysfunction in Alzheimer's disease

Written by - Wang Qi, Su Yixun Editor-in-Charge - Wang Sizhen Editor - Xia Ye

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss and cognitive impairment
.
Because the mechanism of the disease has not yet been dissected, treatment of AD still faces great challenges [1-3
].
Blood-brain barrier (BBB) dysfunction is one of the pathological features of Alzheimer's disease and an important contributor to its progression, especially in the early stages [4].

However, the current insufficient research on the regulatory mechanism of the change of blood-brain barrier function in AD has hindered further research on the targeted regulation of blood-brain barrier function to delay the progression of AD disease
.

Recently, Yi Chenju's team from the Seventh Affiliated Hospital of Sun Yat-sen University and Niu Jianqin team from the Army Military Medical University jointly published an article entitled "Activation of Wnt/β-catenin pathway mitigates blood-brain barrier dysfunction in Alzheimer's disease" at Brain
.
This study confirmed dysfunction
of BBB and brain endothelial cells (BEC) in brain samples in AD patients.
In the mouse model of AD (APP/PS1), BBB dysfunction and BEC damage in the early course of the disease were found and progressively worsened
with age.
It was further found that Aβ oligomers act directly on endothelial cells to inhibit their Wnt/β-catenin signaling, thereby disrupting blood-brain barrier function
.
The researchers used optogenetic tools to target activation of the Wnt/β-catenin pathway in BEC and found that Aβ oligomer-induced lesions
could be restored.
It is suggested that the Wnt/β-catenin pathway in endothelial cells has become a potential new target for AD drug development, and timely restoration of BBB function is a new strategy
for early intervention in the treatment of AD.
(Further reading: Niu Jianqin's team's latest research results, see "Logical Neuroscience" report (click to read): Mol Psychiatry-Niu Jianqin/Xiao Lan's team found that oligodendroglial precursor cells DISC-Δ3 variable shear inhibits excitatory synaptic growth leading to schizophrenia )

The authors first had BBB dysfunction in brain tissue samples from AD patients, manifested by the accumulation of hematogenous fibrinogen in the hippocampus and cerebral cortex perivascular formation, accompanied by downregulation of the expression of the compact neximen CLDN5 and glucose transporter GLUT1 in BEC, suggesting impairment of BEC and BBB function in AD pathology (Figure 1).

Figure 1 Blood-brain barrier barrier disorders in the hippocampus in AD patients

(Source: Q.
Wang et al.
, Brain, 2022）

Similarly, this phenomenon was observed in AD mouse model APP/PS1 mice, and BEC and BBB dysfunction appeared early
in the course of the disease.
In APP/PS1 mice, Aβ plaques accumulate with age, and hippocampus can be observed at 4 months of age to begin to produce Aβ plaques
.
The authors found that significant bloodborne fibrinogen leakage was detected extravascular in the hippocampal region of APP/PS1 at 4 months of age, and that the expression of GLUT1 and CLDN5 in BEC was down-regulated and worsened with the increase of age in mice
.
Suggests abnormal blood-brain barrier function early in the onset of AD and progressively worsens as the course progresses (Figure 2
).

Figure 2 Blood-brain barrier disorders in APP/PS1 mice

(Source: Q.
Wang et al.
, Brain, 2022）

The authors further found that the Wnt/β-catenin signal of BEC in AD patients and mouse models APP/PS1 was down-regulated
.
The treatment of primary BEC with dissolved Aβ oligomers in vitro can inhibit its Wnt/β-catenin signaling pathway and lead to downregulation and dysfunction
of GLUT1 and CLDN5 expression.
Explain that in AD pathology, dissolved Aβ oligomers can directly inhibit the Wnt/β-catenin signaling pathway in BEC, resulting in BEC functional impairment and BBB dysfunction (Figure 3).

Figure 3 The soluble Aβ oligomer in AD inhibits the Wnt/β-catenin signal pathway in BEC, resulting in BEC functional impairment

(Source: Q.
Wang et al.
, Brain, 2022）

So, can activating the Wnt/β-catenin signaling pathway of BEC in the pathological environment of AD improve BBB dysfunction? To answer this question, the authors developed the optogenetics tool OptoLRP6, which can specifically activate the Wnt/β-catenin pathway under blue light activation, and found in vitro experiments that activating the Wnt/β-catenin signaling pathway in BEC can prevent and treat BEC and BBB dysfunction caused by Aβ oligomers (Figure 4).

Figure 4 Optogenetically activated BEC's Wnt/β-catenin signaling pathway improves BBB dysfunction

(Source: Q.
Wang et al.
, Brain, 2022）

Figure 5 Graphic summary

(Source: Q.
Wang et al.
, Brain, 2022）

Conclusion and discussion, inspiration and prospects, this study confirms that in the Alzheimer's disease (AD) brain, lytic Aβ oligomers inhibit the Wnt/β-catenin signaling pathway in brain endothelial cells (BEC), leading to BEC functional impairment and BBB dysfunction
.
Using optogenetics-specific activation of Wnt/β-catenin signaling in BEC, Aβ-induced BEC functional impairment can be reversed and prevented to alleviate BBB dysfunction (Figure 5).

The optogenetic tool OptoLRP6 developed in this study can accurately regulate the activation of Wnt/β-catenin signals in time and degree, which has potential application value in AD prevention and control.
Timely restoration of BBB function is a new strategy
for early intervention in the treatment of AD.
Future research can further focus on whether activating the Wnt/β-catenin signaling pathway of BEC in the AD model can delay the pathology of AD and cognitive function in animals
.

Original link: https://doi.
org/10.
1093/brain/awac236

Wang Qi, a postdoctoral fellow in Yi Chenju's research group of the Seventh Affiliated Hospital of Sun Yat-sen University, and Huang Xiaomin, an intern researcher, are co-first authors
.
Professor Alexei Verkhratsky, University of Manchester, Professor Niu Jianqin of Army Military Medical University, and Lead Contact, Associate Researcher of the Seventh Affiliated Hospital of Sun Yat-sen University, are the corresponding authors
of this paper.

Corresponding authors: Yi Chenju (left), Niu Jianqin (center), Alexei Verkhratsky (right)

(Photo courtesy of: Yi Chenju/Niu Jianqin/Alexei Verkhratsky Team)

About the Author (Swipe Up and Down to Read)

Yi Chenju (PhD, MD), Associate Researcher, Independent PI, Doctoral Supervisor
.
He has won the "Jieqing" of Guangdong Province, the "Youqing" of Shenzhen, the overseas high-level talents of Shenzhen, and the outstanding talents of the "Hundred Talents Plan" of Sun Yat-sen University
.
In 2011, he received his Ph.
D.
in Neurology from Tongji Hospital of Huazhong University of Science and Technology and his M.
D.
from the University of Tübingen, Germany.

He then worked as a postdoctoral fellow at the Collège de France and the French Academy of Sciences in Paris, France, and Senior Research Fellow
at the Life Research Centre of the National University of Singapore.
At the end of 2018, a research group was established in the Seventh Affiliated Hospital of Sun Yat-sen University, mainly engaged in the study of the
mechanism of glial cells in central nervous system diseases.
He has published more than 50 articles in EMBO J, Brain, Ann Neurol, Adv Sci, Cell Death Differ, Glia and other magazines
.

Niu Jianqin: Professor, Bo's native tutor, deputy director
of the Department of Histology and Embryology of the Army Military Medical University.
He was selected as a young Yangtze River scholar of the Ministry of Education of the People's Republic of China, and
a Chongqing elite.
He has successively gone to France Public College in France and the University of California, San Francisco to carry out postdoctoral research
.
In recent years, he has focused on the developmental process of "migration-proliferation-differentiation" of oligodendroglial precursor cells of the central nervous system, the regulatory mechanism, and the new role
involved in the development of the disease process.
Studies have been published
in the journals Science, Nature Neuroscience, Neuron, Advanced Science, Molecular psychiatry, Brain, Glia and others.

Alexei Verkhratsky: Fellow of the European Academy of Sciences, Fellow of the German Academy of Sciences, Fellow of the Royal Spanish Academy of Sciences, Professor of Neurophysiology at the Faculty of Life Sciences, University of Manchester, UK, is an internationally recognized leader in the field of cell neurophysiology
.
He has made important contributions
in the field of chemical and electrical signaling of neuron-glial communication and the role of intracellular calcium signaling in the process of neurological integration.
He has published more than 220 papers in Lancet Neurol, Nat Neurosci, Neuron, Trends Neurosci, Acta Neuropathol, etc

Selected articles from previous issues[1] Prog Neurobiol Frontier ThinkingEffects of genetic factors, aging and intestinal microbial disorders on immune responses in "dry" and "wet" retinal degenerative degeneration[2] Sci Adv-Xi Zhengxiong's team discovered a new mechanism of sports reward: midbrain red nucleus - ventral covered area glutamate neural pathway [3] Mol Psychiatry - Niu Jianqin / Xiao Lan's team found that the oligodendroglial precursor cell DISC-Δ3 variable shear inhibits excitatory synaptic growth leading to schizophrenia [4] PNAS | Sun Bo's research group and collaborators found that time signals are the main factors regulating multicellular information networks[5] Cell Reports—Liu Sheng/Liu Yizhi's team mapped mammalian retinal ganglion cell multimodal maps[6] Cereb Cortex - default mode network brain imprint in patients treated with depression with electrical shock [7] Mol Psychiatry - Xiong Wei's research group to analyze the neural loop mechanism of fear enhancing shock reflex [8] Transl Psychiatry—Early Damage to Cortical Circuit Plasticity and Connectivity in Mouse Models of Alzheimer's Disease[9] J Neurosci—Li Shao/Ma Tonghui's team revealed the orthogonal array structure of AQP4 in mouse with aquaporin point mutation and depolymerization of mice and reduced its polarity distribution at the astrocyte endpodia [10] Cereb Cortex - Yu Yuguo team worked together to build a human brain energy and activity map to reveal the law of energy distribution Quality scientific research training course recommendation [1] Symposium on Patch Clamp and Optogenetics and Calcium Imaging Technology (October 15-16, 2022, Tencent Conference)【2】R Language Clinical Prediction Biomedical Statistics Special Training (October 15-16, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing) Conference/Forum Preview & Review

[1] Trailer | Conference on Neuromodulation and Brain-Computer Interface (U.
S.
Pacific Time: October 12-13), Beijing Time[
2] Conference Report - The human brain and machine are gradually approaching, and the "black technology" of brain-computer interfaces shines into reality

Welcome to "Logical Neuroscience" [1] Talent Recruitment - "Logical Neuroscience" Recruitment Article Interpretation/Writing Position (Network Part-time, Online Office) References (Swipe Up and Down)

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End of article