This review has highlighted the role of Blood- Brain Barrier (BBB) dysfunction in the pathogenesis of Alzheimer’s disease (AD). It has illustrated how BBB dysfunction directly or indirectly can promote amyloid-β (Aβ) accumulation in the brain which can give rise to cognitive impairment and onset of dementia. AD is a progressive neurodegenerative disorder which is characterized by memory impairment, language deterioration, visuospatial deficits, emotional problems, thinking and reasoning problems, and a lack of motivation. Neurofibrillary tangles (NFTs), amyloid-β (Aβ) plaques, neuroinflammation, oxidative stress, loss of synapse, neurodegeneration, etc. are the key neuropathological markers of AD. BBB deterioration and dysfunction is one of the most common pathophysiologic characteristic of neurodegenerative process of AD.
The key role of BBB is safeguarding and maintaining brain health microenvironment to run proper function of neuron and neural signalling. Among three brain barriers such as arachnoid barrier, blood-CSF barrier and BBB, the BBB plays the most important role and a highly selective semi-permeable structural and chemical barrier that separates the circulating blood from the brain and extracellular fluid (ECF). It is a dynamic interface between the central nervous system (CNS) and peripheral circulation. Certain anesthetics, O2, CO2 and fat soluble substances are able to pass through the BBB while penicillin, HCO3- ions, fat insoluble substances are not. Under pathological circumstances such as brain edema, tumors, inflammation, etc., the BBB becomes more permeable. In AD, BBB breakdown activates β-secretase and ꙋ-secretase and leads to the over-production of Aβ.
Among other BBB transporters, receptor foe advanced glycation end products (RAGE) and low density lipoprotein 1 (LRP1) are critical for regulating Aβ homeostasis in brain. In addition to increased influx at the BBB and neuroinflammation, their secondary effects can also result in oxidative injury. The Aβ trafficking regulated by LRP1 at the BBB is associated with apolipoprotein in a way that Aβ40 binding to apolipoprotein E (APoE) weakens Aβ40 efflux whereas Aβ42 binding to apolipoprotein J (APoJ) promotes Aβ42 efflux rate. RAGE is a multiligand (such as Aβ, β-sheet fibrils, S100 proteins and others) receptor of immunoglobulin superfamily. It has two functional categories: cell membrane-bound (full length) and soluble (sRAGE). Aβ-ligand binding to full length RAGE promotes AD pathological injury resulting in neuroinflammation and increase in RAGE expression. Whereas, sRAGE may blockade Aβ- RAGE interaction and prevent extracellular Aβ into cells or circulating Aβ into brain parenchyma. However, reduced level of sRAGE has been reported in the plasma of patients with AD. Among other BBB transporters, ATP-binding cassette (ABC) proteins such as ABCA1, P-gp/ABCBI and BCRP/ABCG2 are involved in lowering Aβ burden in the brain.
Pericytes, an important contractile component of the BBB and the neurovascular unit, act like the gatekeepers of the BBB and exquisitely regulate the movement of brain cells and the transportation of nutrients and molecules including Aβ into the blood from the brain interstitial fluid that surrounds the brain cells. In AD with APoE4 carriers, pericyte degradation and BBB collapse have been observed to be accelerated. Astrocytes play a crucial role among the three primary BBB cells (such as capillary endothelial cells, perivascular pericytes, and astrocyte end-feet), and their dysfunction promotes RAGE activity and lowers the activity of LRP1. Tight junctions (TJs) at the BBB selectively exclude most blood-borne substances from entering the brain, therefore maintaining BBB structural integrity. RAGE mediated Aβ cytotoxicity causes disruption of TJ of the BBB via Ca2+ -calcineurin signalling. Overexpression of occluding, a TJ protein, was found in both AD and vascular dementia. Deficiency of other TJ proteins such as claudin-5 and claudin-12 in the choroid plexus and the BBB leads to increased BBB permeability in the hippocampal area. In addition, Aβ induced increase in matrix metalloprotease 9 (MMP9) activity disrupts claudin-5. Furthermore, Aβ oligomers mediated over-activation of the matrix-metalloproteinases (MMPs) degrades both the extracellular matrix and TJ between endothelial cells.
On the other hand, excessive Aβ generation, deposition, and accumulation enhance the damage of neurovascular units and lead to pericyte death, astrocyte dysfunction, and/or loss of transport function from vascular endothelial cells. In response to Aβ accumulation, transendothelial migration of monocytes increases across the BBB, which is associated with the pathophysiology of Aβ-related vascular disorder. It can be suppressed by inhibitors of protein kinase C and intensified by phosphatase inhibitors. Additionally, Aβ induces expression of vascular adhesion molecules, promoting leukocyte adhesion and transmigration during the pathological process of AD. Recently, it has been reported that Aβ42 enhances BBB damage by inducing RhoA activation.
Regarding BBB dysfunction and tau pathology, BBB dysfunction causes tau hyperphosphorylation, to build neurofibrillary tangles (NFTs), which can also cause BBB damage and culminate in a detrimental feed-forward cycle, thus gives rise to cognitive impairment and the onset of dementia. Aβ pathology suffering from BBB dysfunction indirectly facilitates the onset of tau pathology. Furthermore, several tau proteins, truncated tau cross the BBB bi-directionally, thus blood-borne tau proteins enhance brain tau pathology. Consequently, a vicious circle between the Aβ pathology and BBB damage has been established, which will proceed to destroy the neurons and glia cells and damage the neural networks.
Reference:
Cai, Zhiyou; Qiao, Pei-Feng; Wan, Cheng-Qun; Cai, Min; Zhou, Nan-Kai; Li, Qin (2018). Role of Blood-Brain Barrier in Alzheimer’s Disease. Journal of Alzheimer's Disease, 63(4), 1223–1234. doi:10.3233/JAD-180098
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