The contribution of β-amyloid, Tau and α-synuclein to blood–brain barrier damage in neurodegenerative disorders

Abstract

Central nervous system (CNS) accumulation of fibrillary deposits made of Amyloid β (Aβ), hyperphosphorylated Tau or α-synuclein (α-syn), present either alone or in the form of mixed pathology, characterizes the most common neurodegenerative diseases (NDDs) as well as the aging brain. Compelling evidence supports that acute neurological disorders, such as traumatic brain injury (TBI) and stroke, are also accompanied by increased deposition of toxic Aβ, Tau and α-syn species. While the contribution of these pathological proteins to neurodegeneration has been experimentally ascertained, the cellular and molecular mechanisms driving Aβ, Tau and α-syn-related brain damage remain to be fully clarified. In the last few years, studies have shown that Aβ, Tau and α-syn may contribute to neurodegeneration also by inducing and/or promoting blood–brain barrier (BBB) disruption. These pathological proteins can affect BBB integrity either directly by affecting key BBB components such as pericytes and endothelial cells (ECs) or indirectly, by promoting brain macrophages activation and dysfunction. Here, we summarize and critically discuss key findings showing how Aβ, Tau and α-syn can contribute to BBB damage in most common NDDs, TBI and stroke. We also highlight the need for a deeper characterization of the role of these pathological proteins in the activation and dysfunction of brain macrophages, pericytes and ECs to improve diagnosis and treatment of acute and chronic neurological disorders.

CNS-associated macrophages contribute to intracerebral aneurysm pathophysiology

“…CAMs are a distinct population of brain resident macrophages located within CNS interfaces, which include the perivascular spaces (perivascular macrophages, PVMs), the leptomeninges (meningeal macrophages, MMs), and the choroid plexus (choroid plexus macrophages, ChPM) and are identified in human and mouse brain as CD163 + and CD206 + cells, respectively [ 12 ]. Recent studies have indicated that CAMs are involved in a wide variety of pathological states [ 8 , 9 , 23 , 48 ]. Their main functions, as described to date, include regulation of blood–brain barrier (BBB) integrity and cerebrospinal fluid (CSF) dynamics, phagocytosis of blood-borne pathogens, and control of leukocyte migration [ 10 , 27 ].…”

Pharmacological Activities and Molecular Mechanisms of Sinapic Acid in Neurological Disorders

“…The cellular antioxidant system, composed of superoxide dismutase (SOD), catalase (CAT), peroxidase, and reduced glutathione (GSH), acts as a free radical scavenger, and neurodegeneration is promoted due to an imbalance in the defensive actions of antioxidants and overproduction of ROS. , Moreover, neuroinflammation, which is initially crucial for stimulating tissue repair and removing the brain’s cellular waste, could be a significant key factor in the pathogenesis and progression of various NDs in cases of persistence due to genetic mutations, trauma, and infection, which play their roles via proinflammatory agent release, including interleukin-6 (IL-6) and immune cell activation, leading to neuronal dysfunction and destruction. In fact, the engagement and overactivity of microglia and astrocytes in neuroinflammatory responses might be responsible for the pathogenesis of neurodegenerative diseases, especially Alzheimer’s disease, in which microglia play a vital role in responding to Aβ aggregation. − The major NDs include Alzheimer’s disease (AD), Parkinson’s disease (PD), ataxia, Huntington’s disease (HD), motor neuron disease, multiple system atrophy, and progressive supranuclear palsy, in which the main causes are reported to be the accumulation of amyloid β (Aβ), Tau, and α-synuclein in the form of insoluble fibrillary deposits with β-sheet structure in the brain of patients. , According to the Global Burden of Disease (GBD) study, a variety of conditions, including AD, PD, multiple sclerosis (MS), and epilepsy, as well as headache disorders such as migraine, tension-type headache, and medication-overuse headache, collectively contribute to 3% of the GBD. The top 50 causes of disability-adjusted life years (DALYs) include dementia, epilepsy, migraine, and stroke…”

“…disease (PD), ataxia, Huntington's disease (HD), motor neuron disease, multiple system atrophy, and progressive supranuclear palsy, in which the main causes are reported to be the accumulation of amyloid β (Aβ), Tau, and α-synuclein in the form of insoluble fibrillary deposits with β-sheet structure in the brain of patients. 11,12 According to the Global Burden of Disease (GBD) study, a variety of conditions, including AD, PD, multiple sclerosis (MS), and epilepsy, as well as headache disorders such as migraine, tension-type headache, and medication-overuse headache, collectively contribute to 3% of the GBD. The top 50 causes of disability-adjusted life years (DALYs) include dementia, epilepsy, migraine, and stroke.…”