The role of extracellular matrix alterations in mediating astrocyte damage and pericyte dysfunction in Alzheimer's disease: A comprehensive review

• Published in: The European journal of neuroscience 2022-11, Vol.56 (9), p.5453-5475
• Main Authors: Anwar, Mai M., Özkan, Esra, Gürsoy‐Özdemir, Yasemin
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - metabolism; Alzheimer's disease; Astrocytes; Astrocytes - metabolism; astrocytes pericytes; basement membrane; BBB dysfunction; Blood-brain barrier; Blood-Brain Barrier - metabolism; Brain - metabolism; Brain injury; Cognitive ability; Endothelial cells; Endothelial Cells - metabolism; Extracellular matrix; Extracellular Matrix - metabolism; Extracellular Matrix - pathology; Humans; Inflammation; Neurodegenerative diseases; Neurotoxicity; Pericytes; Pericytes - metabolism; Pericytes - pathology; Tight junctions
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/ejn.15372

The brain is a highly vascularized tissue protected by the blood–brain barrier (BBB), a complex structure allowing only necessary substances to pass through into the brain while limiting the entrance of harmful toxins. The BBB comprises several components, and the most prominent features are tight junctions between endothelial cells (ECs), which are further wrapped in a layer of pericytes. Pericytes are multitasked cells embedded in a thick basement membrane (BM) that consists of a fibrous extracellular matrix (ECM) and are surrounded by astrocytic endfeet. The primary function of astrocytes and pericytes is to provide essential blood supply and vital nutrients to the brain. In Alzheimer's disease (AD), long‐term neuroinflammatory cascades associated with infiltration of harmful neurotoxic proteins may lead to BBB dysfunction and altered ECM components resulting in brain homeostatic imbalance, synaptic damage, and declined cognitive functions. Moreover, BBB structure and functional integrity may be lost due to induced ECM alterations, astrocyte damage, and pericytes dysfunction, leading to amyloid‐beta (Aβ) hallmarks deposition in different brain regions. Herein, we highlight how BBB, ECM, astrocytes, and pericytes dysfunction can play a leading role in AD's pathogenesis and discuss their impact on brain functions. Extracellular matrix (ECM) modifications act as a predisposing factor for Alzheimer's disease (AD). These structural modifications lead to blood–brain barrier (BBB) disruption, followed by macrophages infiltration, pericytes damage, reactive astrocytes/microglia activation, increased oxidative stress, and inflammatory cytokines release. Brain inflammatory released cytokines affect ECM structural components resulting in increased Aß deposition, brain atrophy, and cognitive dysfunction.