Review of Neural Regen Res︱Guo Junhong's team focuses on the interaction between β-amyloid and cerebral vascular endothelial cells in Alzheimer's disease

Written by ︱Wang Zhuoran, edited by Zhang Yanli︱Wang Sizhen Alzheimer's disease (AD) is a degenerative disease of the central nervous system, with progressive memory and cognitive function decline as the main clinical manifestations, is the most important Alzheimer's disease.
form [1]
.

At present, AD still lacks effective treatment methods, and the clinically available drugs can only temporarily relieve the symptoms and cannot completely reverse the development of AD disease [2]
.

A large amount of β-amyloid (Aβ) deposition in the brain is a major pathological feature of AD, and is also considered to be a driving factor for the occurrence and development of AD
.

Therefore, preventing the accumulation of Aβ in the brain and promoting the clearance of Aβ is an important strategy for the research and treatment of AD [3]
.

 The imbalance between the production and clearance of Aβ, especially the disorder of Aβ clearance, is the key factor leading to the deposition of Aβ in the brain of AD patients and eventually the formation of plaques[4,5]
.

The transport of Aβ across the blood-brain barrier is one of the main ways to mediate the transport and clearance of Aβ in the brain to the periphery, and the damage of the blood-brain barrier has an important impact on the pathogenesis of AD
.

Neurovascular dysfunction is an important manifestation of the damaged blood-brain barrier in AD, and the abnormal accumulation of Aβ around the neurovascular unit is also an important pathological feature of AD and amyloid cerebrovascular disease
.

Vascular endothelial cells, as the main components of neurovascular units, play an important role in the transport and clearance of Aβ across the blood-brain barrier.
At the same time, Aβ deposited in cerebral blood vessels can also damage vascular endothelial cells, which in turn triggers neurovascular inflammation, leading to Neurodegeneration, etc.
, but the specific mechanism of the above process is still unclear [6,7]
.

Therefore, understanding the clearance of Aβ across the blood-brain barrier mediated by cerebral vascular endothelial cells and their receptors and transporters, as well as the potential interaction mechanism of Aβ and vascular endothelial cells, may provide new insights for the targeted clearance of Aβ in the brain of AD patients.
ideas
.

 On April 1, 2022, Guo Junhong's research group from Shanxi Medical University recently published a review article entitled "The relationship between amyloid-beta and brain capillary endothelial cells in Alzheimer's disease" in "Neural Regeneration Research"
.

Zhang Yanli is the first author of the paper, and Professor Guo Junhong and Dr.
Su Qiang are the co-corresponding authors
.

This article elaborates on the possible mechanism of Aβ clearance in AD, especially the relationship between Aβ and cerebral vascular endothelial cells
.

At the same time, from the perspective of restoring the transport of damaged Aβ across the blood-brain barrier, potential therapeutic targets and new research strategies are proposed for targeting Aβ clearance in the brain of AD patients
.

(Extended reading: For the latest review by Guo Junhong's group, please refer to the "Logical Neuroscience" report: Neurosci Bull Review︱Research progress, problems and prospects of Alzheimer's disease humoral biomarkers) Research progress 1.
Aβ production and removal of starch APP-like precursor protein (APP) is a transmembrane protein that is abundantly expressed in the brain
.

However, in the disease state, APP can be abnormally cleaved by β-secretase and γ-secretase to generate Aβ, and soluble Aβ is further deposited to form Aβ plaques
.

The aggregation of Aβ can promote the phosphorylation of tau protein in neurons, cause neuronal synaptic dysfunction, damage the long-term potentiation of the hippocampus, induce a series of pathological changes such as oxidative stress and neuroinflammation, and eventually lead to neuronal apoptosis [8]
.

In most late-onset sporadic AD, the production rate of Aβ remains relatively constant, but the clearance rate decreases significantly [9]
.

Therefore, Aβ clearance disorder is considered to be the main reason for the massive deposition of Aβ in AD brain, and it is also a key factor leading to the occurrence and development of AD
.

Under normal circumstances, Aβ in the brain can be cleared by a variety of mechanisms, including intracellular clearance (ubiquitin-proteasome pathway and autophagy-lysosomal pathway), extracellular protease degradation (including insulin-degrading enzymes, enkephalinases) and angiotensin-converting enzyme), phagocytosis and uptake by microglia or astrocytes, transport to peripheral organs and tissue clearance, etc.
[10]
.

Among them, the transport of Aβ in the brain to the peripheral clearance is considered to be an important pathway for Aβ clearance, including the blood-brain barrier pathway, the blood-cerebrospinal fluid barrier pathway, the arachnoid granule pathway, and the lymphatic-related pathway [11]
.

 2.
Cerebral vascular endothelial cells mediate Aβ transport and clearance Studies have shown that the blood-brain barrier plays an important role in the peripheral transport and clearance of Aβ[12]
.

As an important component of the blood-brain barrier, vascular endothelial cells express specific transporters and transcellular receptors, supply nutrients in the blood to the brain and transport metabolites in the brain to the peripheral blood [1]
.

Aβ can be transported and cleared through the blood-brain barrier, first through the membrane of cerebral vascular endothelial cells (brain tissue side) into the cytoplasm, and then through the luminal side membrane to the peripheral blood [13].
Aβ may be directly cleared by the endo-degradation system of endothelial cells
.

Receptors such as low-density lipoprotein receptor-related protein 1 (LRP1), receptor for advanced glycation end-products (RAGE), major histocompatibility complex class I-related protein (FcRN), and ATP-binding cassettes have been found.
P-gp (also known as ABCB1), ABCA1, breast cancer resistance protein (BCRP, also known as ABCG2) and ABCC1 in the (ABC) transporter may be involved in the transport and clearance of Aβ across cerebral vascular endothelial cells
.

Figure 1 Receptors and transporters mediate the transport of Aβ across the blood-brain barrier (Source: Zhang YL, et al.
, Neural Regen Res, 2022) (1), receptor-mediated transcellular transport of Aβ clearance is a receptor A common pathway for mediated Aβ transport across the blood-brain barrier, that is, one side membrane receptor binds to Aβ and internalizes to form endocytic vesicles, which are transported to the opposite side membrane and fuse and release Aβ
.

Brain vascular endothelial cells express abundant Aβ receptors.
The receptors on the surface of transmembrane cells on endothelial cells are first synthesized on the endoplasmic reticulum, then transferred to the Golgi for glycosylation, and then transported to the cell membrane to participate in cell signal transduction and ligand internalization
.

After internalization of receptor-ligand complexes, it can be degraded and cleared through the endosome/lysosomal pathway of intracellular degradation, and it can also be used for transcellular transport and receptor recycling through other pathways [1]
.

It has been found that members of the low-density lipoprotein receptor family, especially LRP1, are the main receptors involved in the transport of Aβ across the blood-brain barrier, which can mediate the peripheral transport of Aβ across the blood-brain barrier
.

FcRN is an Aβ receptor expressed on the side membrane of brain tissue of cerebral vascular endothelial cells, which can rapidly transport immune complex IgG-Aβ to peripheral blood
.

On the other hand, vascular endothelial cells also express RAGE receptors that transport Aβ from the periphery to the brain on the luminal side membrane, and transport Aβ from the periphery to the brain through endocytosis
.

Under normal circumstances, these Aβ receptors expressed in cerebral vascular endothelial cells play a key role in maintaining Aβ balance in the brain, but in disease states such as AD, their expression and function are severely damaged [14, 15]
.

 (2) ABC transporter-mediated Aβ clearance ABC transporter is a multi-domain integrated membrane protein that utilizes the energy generated by the hydrolysis of adenosine triphosphate to transport substances through the cell membrane
.

ABC transporters have a specific molecular structure, including two nucleotide-binding domains and two transmembrane domains, the former provides the driving force for transport, and the latter facilitates the transport of substrates across lipid membranes
.

ABC transporters are mainly expressed on the luminal side or brain tissue side membrane of cerebral vascular endothelial cells.
Studies have shown that a variety of transporters such as P-gp, ABCA1, ABCG2 and ABCC1 have the properties of binding and transporting Aβ[16]
.

P-gp, ABCG2 and ABCC1 can participate in the peripheral transport of Aβ across the blood-brain barrier by cooperating with LRP1
.

LRP1 mediates Aβ endocytosis in the brain.
After Aβ is transported to the luminal side of vascular endothelial cells, it can be assisted by P-gp, ABCG2 and ABCC1 to transport Aβ to peripheral blood
.

Changes in the expression or activity of ABC transporters in cerebral vascular endothelial cells may lead to the clearance of Aβ in the brain.
Therefore, ABC transporters are also important targets for maintaining the homeostasis of Aβ in the brain
.

 3.
Effects of Aβ on cerebrovascular endothelial cells of AD patients Cerebrovascular endothelial cells play an important role in regulating cerebral blood flow and mediating the exchange of substances across the blood-brain barrier, maintaining the dynamic balance of substances in blood and brain tissue
.

Aβ deposition impairs the structure and function of vascular endothelial cells and alters cerebral blood circulation
.

The specific manifestations are as follows: ① It affects the expression of Aβ receptors and transporters in cerebral vascular endothelial cells and hinders the clearance of Aβ in the brain
.

For example, the increase of Aβ can induce the increase of RAGE expression, while the expression of LRP1 and P-gp is down-regulated
.

RAGE can trigger oxidative stress and mediate Aβ-induced neurotoxicity, amplify Aβ-induced microglial inflammation and monocyte migration across brain vascular endothelial cells [17,18]
.

The decreased expression of LRP1 and P-gp will reduce the clearance rate of Aβ in the brain[19]
.

② Induce oxidative stress in cerebral vascular endothelial cells
.

It causes DNA damage, damage to the blood-brain barrier structure and disruption of cerebral blood flow [20-22]
.

③ Stimulate vascular endothelial cells to release inflammatory mediators
.

Aβ increases the permeability of the blood-brain barrier, allowing leukocytes to enter the central nervous system and trigger a neuroinflammatory response.
It also promotes the adhesion of leukocytes by inducing the expression of endothelial cell selectin, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1.
and transport, thereby inducing chronic neuroinflammation [23]
.

④ The deposited Aβ destroys the tight junction and adhesion junction complex of cerebral vascular endothelial cells
.

Resulting in pericyte degeneration and reduced coverage, disproportion of the basement membrane, loss of aquaporin 4, and depolarization of the terminal foot processes of astrocytes, these structural changes contribute to the physical degeneration of the blood-brain barrier, leading to perivascular edema, Vascular inflammation, and decreased cerebral blood flow [5,24]
.

 4.
Restoring the transport of damaged Aβ across the blood-brain barrier is a potential strategy for AD treatment as a potential target for the treatment of AD
.

① Up-regulation of LRP1 expression level: LRP1 can improve the transport of Aβ across the blood-brain barrier
.

Novel drugs and/or gene therapy to restore LRP1 levels may be potential targets for the treatment of AD; in addition, phosphatidylinositol-binding protein (PICALM), which is abundantly expressed in cerebral vascular endothelial cells, regulates the Aβ-LRP1 complex across vascular endothelial cells Therefore, PICALM may also be another potential therapeutic target to promote Aβ clearance [11]
.

② Improve the activity of P-gp: P-gp can reduce Aβ brain load
.

Pregnane X receptor (PXR) is a ligand-activated nuclear receptor that can upregulate P-gp expression and improve its function, thereby promoting Aβ efflux in the brain [25]
.

③ Induction of ABCA1 expression: The decrease of ABCA1 protein level promotes the accumulation of Aβ in the brain
.

Liver X receptor (LXR) can induce the expression of ABCA1, so activation of LXR to mediate the upregulation of ABCA1 may be a potential target for reducing Aβ levels in the brain [26]
.

④ Reduce the activity of RAGE: RAGE mediates the transport of peripheral Aβ into the brain and promotes the deposition of Aβ in the brain
.

Some tertiary amine compounds selected by drug screening can inhibit the interaction between RAGE and Aβ and prevent Aβ from re-entering the brain [27]
.

In addition, down-regulating the expression of cerebrovascular endothelial chemokine receptor 5 (CCR5) can prevent the Aβ-RAGE complex from transmitting signals to the immune system, and may also become a new target for the treatment of AD [14]
.

Currently, approved AD drug treatment strategies can only provide symptomatic relief, and existing clinical trials lack intervention in the early stages of AD, and future treatment strategies should aim to prevent the initial deposition of Aβ and, therefore, restore defective receptors and A transporter-mediated Aβ clearance pathway to prevent initial Aβ deposition may slow or prevent AD progression [28]
.

 Figure 2 Receptors and transporters on endothelial cells may be potential targets for Aβ clearance therapy (Source: Zhang YL, et al.
, Neural Regen Res, 2022) Summary and Outlook The mechanism of Aβ transport and clearance across the blood-brain barrier mediated by receptors and transporters expressed by vascular endothelial cells is expected to provide a new strategy for the clinical treatment of promoting Aβ clearance in the brain of AD patients
.

However, the discussion of blood-brain barrier-mediated Aβ clearance in this paper is limited to the role of cerebrovascular endothelial cells, and the role of other components of the blood-brain barrier has not been fully discussed, and there are certain limitations
.

In the future, the regulatory role of cerebral vascular endothelial cells and neurovascular units in AD will still be a very promising research direction: such as further exploring the mechanism of Aβ transport by receptors or transporters expressed on cerebral vascular endothelial cells, especially It is the intracellular mechanism mediated by these proteins; to clarify the potential changes and regularities of the expression and function of cerebral vascular endothelial cell receptors and ABC transporters in different stages of AD process; to seek the structural and functional changes of brain neurovascular units in the early stage of AD biomarkers
.

These studies may provide an important theoretical basis for explaining the function of neurovascular units in the AD brain
.

 Link to the original text: https://doi.
org/10.
4103/1673-5374.
335829 Guo Junhong (Photo provided by: Guo Junhong Laboratory of Shanxi Medical University) Guo Junhong, female, doctor of neurology, chief physician, doctoral tutor; The First Hospital of Shanxi Medical University Director of the Department of Neurology; Deputy Director of the Shanxi Provincial Key Laboratory of Brain Science and Neuropsychiatric Diseases; Member of the Neurology Professional Committee of the Chinese Medical Association; Member of the Neurology Professional Committee of the Chinese Medical Doctor Association; Member of the Neuromyopathy Group of the Neurology Branch of the Chinese Medical Association; Member of the Amyotrophic Lateral Sclerosis Collaborative Group of the Chinese Medical Association; Member of the Peripheral Neuropathy Collaborative Group of the Chinese Medical Association; Member of the Standing Committee of the Rare Diseases Committee of the Chinese Rare Diseases Nervous System; Member of the Neuroimmunology Branch of the Chinese Society of Neuroscience; Member; Director of the National Training Center for Peripheral Neuropathy Diagnosis and Treatment; Member of the Chinese Medical Association Medical Appraisal Expert Bank; Chairman-designate of the Neurology Branch of the Shanxi Medical Association; Editorial Board Member of the Chinese Journal of Neurology; My specialty: diagnosis of difficult diseases of the nervous system , the research direction is neuromuscular disease, cognitive impairment, cerebrovascular disease
.

16 SCI papers, 8 projects in charge
.

Talent Recruitment [1] "Logical Neuroscience" is looking for associate editor/editor/operation position (online office) Selected articles from previous issues [1] Neuron︱Chen Tao/Li Yunqing/Zhuo Min's research group cooperates to reveal the synaptic effect of pain empathy Molecular mechanism【2】Transl Psychiatry︱Li Yan/Zhang Jie’s team used transcutaneous electrical acupoint stimulation for the first time in the treatment of attention deficit hyperactivity disorder in school-aged children【3】Aging Cell Review︱Zhang Hong/Chen Yingzhi/Tian Mei Collaborative Review of Intestines The mechanism of microglia regulating microglia function in cognitive aging [4] Review of Front Cell Neurosci︱Microglia: The Hub of Intercellular Communication in Ischemic Stroke [5] Review of Trends Neurosci︱Biological Clock and Circadian Metabolism of Blood Glucose Rhythm research progress【6】Front Aging Neurosci︱Sun Tao’s research group proposes a new protocol for 11C-PiB-PET imaging for early diagnosis of Alzheimer’s disease Double-edged sword effect in vascular units [8] HBM︱Region-based brain MRI spatial standardization method to achieve accurate registration of brain regions [9]J Neuroinflammation︱Peng Ying's group revealed that microglia mitophagy plays an important role in The regulatory role of morphine-induced central nervous system inflammatory suppression【10】Curr Biol︱ Novelty detection and the relationship between surprise and recency in the primate brain Recommended for high-quality scientific research training courses【1】Patch clamp and optogenetics and calcium Imaging Technology Symposium May 21-22 Tencent Conference References (swipe up and down to read) 1.
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Plate making︱Wang Sizhen end of this articleIn vivo activation of human pregnane X receptor tightens the blood-brain barrier to methadone through P-glycoprotein up-regulation.
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28.
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Anti-Amyloid-β Monoclonal Antibodies for Alzheimer's Disease: Pitfalls and Promise.
Biol Psychiatry 2018, 83(4): 311-319.
Edition by Wang SizhenIn vivo activation of human pregnane X receptor tightens the blood-brain barrier to methadone through P-glycoprotein up-regulation.
Mol Pharmacol 2006, 70(4): 1212-1219.
27.
Behl T, Kaur I, Sehgal A, Kumar A, Uddin MS, Bungau S.
The Interplay of ABC Transporters in Aβ Translocation and Cholesterol Metabolism: Implicating Their Roles in Alzheimer's Disease.
Mol Neurobiol 2021, 58(4): 1564-1582.
28.
van Dyck CH.
Anti-Amyloid-β Monoclonal Antibodies for Alzheimer's Disease: Pitfalls and Promise.
Biol Psychiatry 2018, 83(4): 311-319.
Edition by Wang Sizhenvan Dyck CH.
Anti-Amyloid-β Monoclonal Antibodies for Alzheimer's Disease: Pitfalls and Promise.
Biol Psychiatry 2018, 83(4): 311-319.
Edition by Wang Sizhenvan Dyck CH.
Anti-Amyloid-β Monoclonal Antibodies for Alzheimer's Disease: Pitfalls and Promise.
Biol Psychiatry 2018, 83(4): 311-319.
Edition by Wang Sizhen