Blood-brain barrier disruption: a culprit of cognitive decline?

 I bet your competent? doctor DID NOTHING to solve the blood brain barrier disruption caused by your stroke.

Known for well over a decade: That gives you an idea of how incompetent your doctors and hospital are!

Blood-Brain Barrier Integrity Suffers Days After Ischemic Stroke Leading To Serious Complications May 2013

The latest here:

Blood-brain barrier disruption: a culprit of cognitive decline?

• Ji Che,
• Yinying Sun,
• Yixu Deng &
• Jun Zhang 

Fluids and Barriers of the CNS volume 21, Article number: 63 (2024) Cite this article

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Abstract

Cognitive decline covers a broad spectrum of disorders, not only resulting from brain diseases but also from systemic diseases, which seriously influence the quality of life and life expectancy of patients. As a highly selective anatomical and functional interface between the brain and systemic circulation, the blood-brain barrier (BBB) plays a pivotal role in maintaining brain homeostasis and normal function. The pathogenesis underlying cognitive decline may vary, nevertheless, accumulating evidences support the role of BBB disruption as the most prevalent contributing factor. This may mainly be attributed to inflammation, metabolic dysfunction, cell senescence, oxidative/nitrosative stress and excitotoxicity. However, direct evidence showing that BBB disruption causes cognitive decline is scarce, and interestingly, manipulation of the BBB opening alone may exert beneficial or detrimental neurological effects. A broad overview of the present literature shows a close relationship between BBB disruption and cognitive decline, the risk factors of BBB disruption, as well as the cellular and molecular mechanisms underlying BBB disruption. Additionally, we discussed the possible causes leading to cognitive decline by BBB disruption and potential therapeutic strategies to prevent BBB disruption or enhance BBB repair. This review aims to foster more investigations on early diagnosis, effective therapeutics, and rapid restoration against BBB disruption, which would yield better cognitive outcomes in patients with dysregulated BBB function, although their causative relationship has not yet been completely established.

Introduction

The blood-brain barrier (BBB) is a semi-permeable barrier between the central nervous system (CNS) and the bloodstream, which dynamically and tightly regulates the bidirectional exchange of fluid, molecules, extracellular vesicles (EVs), and cells. Consequently, the BBB protects the CNS from harmful insults by selective substance permeation to prevent the passage of harmful substances into the brain parenchyma, and thereby provides a stable environment essential for maintaining brain homeostasis and function. Since the BBB plays a key role in the communication between the two sides during the physiological processes, its structural and functional damage may influence brain homeostasis, leading to brain dysfunction including cognitive decline.

Cellular components of the BBB

The BBB comprises a cerebrovascular network that forms a structural and chemical barrier. Histologically, it consists of non-fenestrated endothelial cells (ECs), pericytes, astrocyte endfeet, perivascular macrophages, and endothelial and parenchymal basal membranes [1]. Anatomically, the components of the BBB are defined as a part of neurovascular unit (NVU), consisting mainly of specialized ECs that establish intimate interactions with astrocytes and pericytes via basal lamina [2]. The basal lamina, a thin, dense cross-linked network of extracellular matrix proteins, is synthesized by ECs, astrocytes, and pericytes. Its components mainly include laminin, collagen IV, nidogen/entactin, and heparin sulfate proteoglycans. As a scaffold, it adheres those cellular components to provide a structural support for BBB integrity. These cellular components of the NVU can be activated in pathological conditions, which triggers BBB instability and severely damages its integrity. Figure 1 shows an intact BBB structure.

Fig. 1

Schematic representation of the cellular and molecular structure of an intact BBB. The molecular and cellular components constitute an intact BBB which maintain brain homeostasis and function. The distribution of blood vessels and cells are shown on the left, a schematic cross-section of a blood vessel is shown in the center, and the molecular connections between endothelial cells are shown on the right. JAM: junctional adhesion molecule; PECAM: platelet endothelial cell adhesion molecule

Full size image

Cerebrovascular ECs comprise around 5% of brain cells, which constitute the most important component of the BBB. Unlike that in peripheral ECs, the unique lipid composition in cerebrovascular ECs underlies the specific function of the BBB [3]. The ECs maintain BBB integrity through its interactions with astrocytes and pericytes, and regulate cerebral blood flow (CBF) respond to changes in neural activities via the release of vasoactive substances.

Astrocytes are the most abundant cells in the brain, with long processes that form endfeet. These astrocytic endfeet are intimate with the ECs and form a tightly overlapping barrier, which limits paracellular communication and diffusion [4, 5]. The astrocyte-EC complex, as the anatomical support of the BBB, controls the influx and efflux of biological substances at extremely low rates, driving transcellular vesicular transport. This process depends on the glycolytic metabolism of ECs [6]. Interestingly, a specific subset of Dmp1-expressing astrocytes can transfer mitochondria to ECs via their endfeet for maintaining BBB integrity [7]. Astrocytes are also reported to control the vascular tone, and hence CBF, through complex signaling cascades involving calcium elevation, release of arachidonic acid, and production of vasodilatory mediators such as prostaglandin E2 (PGE2), epoxyeicosatrienoic acids, and vasoconstrictive mediator 20-hydroxyeicosatetraenoic acid [8]. Therefore they appear to be essential during the early BBB development, and BBB maintenance and repair later in life.

Pericytes are located on the abluminal side of ECs and embedded in the basement membrane. Although they exist throughout the vascular network, pericytes are most abundantly present in the brain and are recruited during brain development for the stabilization of newly formed blood vessels and the integrity of the BBB. Pericyte-EC interaction is also essential during the BBB development. Initially, adhesion molecule CD146 is expressed in the ECs of immature capillaries in the absence of pericytes; however, once pericytes coverage occurs, CD146 is only detected in the pericytes while not in the ECs. Knockdown of CD146 in mouse ECs results in lower brain endothelial claudin-5 expression and BBB breakdown, whereas conditional deletion of CD146 in pericytes leads to defects in pericyte coverage and BBB integrity [9], suggesting its role in coordinating the pericyte-EC interaction. Furthermore, pericyte-EC interaction via endothelial nitric oxide (NO) synthase (eNOS)-derived NO can promote formation of functional vascular networks [10], implying that restoring pericyte-EC interaction after a stroke may improve brain functional recovery. Pericytes can regulate the BBB-specific gene expression patterns in ECs, promote oligodendrocyte progenitor cell (OPC) differentiation, and induce polarization of astrocytic endfeet [11]. Pericyte-deficient adult brains display ongoing angiogenic sprouting without concomitant cell proliferation, whereas a lack of pericytes recruitment results in increased BBB permeability and rupture of microaneurysms associated with cerebral hemorrhage [12]. Platelet-derived growth factor B (PDGFB) released from ECs is indispensable for the recruitment of pericytes expressing the PDGFB receptor beta (PDGFRβ) during angiogenesis and maintenance of pericyte longitudinal capillary coverage via PDGFB–PDGFRβ signaling. Interestingly, a recent study showed that PDGFB released from ECs in neonatal mice was converted to release from microglia in adult mice [13]. Acute deletion of microglial PDGFB greatly impairs BBB integrity in adult mice but not in newborn ones. In contrast, acute knockdown of endothelial PDGFB severely influences CNS microvasculature in neonatal mice but not the BBB in adult ones [13], suggesting a role of microglia in maintaining the BBB integrity during adulthood, although they are not regarded as a component of the BBB. PDGFB deficiency can lead to an impaired BBB, characterized by a pericyte hypoplasia and a sparse, dilated, and venous-shifted brain microvasculature, as well as the formation of microvascular calcification [14]. Similarly, PDGFRβ knockout models exhibit pericyte deficiency and progressive BBB damage secondary to hemodynamic disturbances [15].