Vascular Risk Factors and Alzheimer’s Disease: Blood-Brain Barrier Disruption, Metabolic Syndromes, and Molecular Links

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder, marked by cortical and hippocampal deposition of amyloid-␤ (A␤) plaques and neurofibrillary tangles and cognitive impairment. Studies indicate a prominent link between cerebrovascular abnormalities and the onset and progression of AD, where blood-brain barrier (BBB) dysfunction and metabolic disorders play key risk factors. Pericyte degeneration, endothelial cell damage, astrocyte depolarization, diminished tight junction integrity, and basement membrane disarray trigger BBB damage. Subsequently, the altered expression of low-density lipoprotein receptor-related protein 1 and receptor for advanced glycation end products at the microvascular endothelial cells dysregulate A␤ transport across the BBB. White matter lesions and microhemorrhages, dyslipidemia, altered brain insulin signaling, and insulin resistance contribute to tau and A␤ pathogenesis, and oxidative stress, mitochondrial damage, inflammation, and hypoperfusion serve as mechanistic links between pathophysiological features of AD and ischemia. Deregulated calcium homeostasis, voltage gated calcium channel functioning, and protein kinase C signaling are also common mechanisms for both AD pathogenesis and cerebrovascular abnormalities. Additionally, APOE polymorphic alleles that characterize impaired cerebrovascular integrity function as primary genetic determinants of AD. Overall, the current review enlightens key vascular risk factors for AD and underscores pathophysiologic relationship between AD and vascular dysfunction.

Central nervous system diseases associated with blood brain barrier breakdown - A Comprehensive update of existing literatures

“…They found out altered expression of lowdensity lipoprotein receptor-related protein 1 and receptor for advanced glycation end products at the microvascular endothelial cells dysregulate Aβ tr ansport across the BBB. Altered brain insulin signaling, insulin resistance, dyslipidemia and white matter lesions contribute to tau and Aβ pathogenesis [29]. Matrix metalloproteinases (MMP) control the functions of a number of signaling and scaffolding molecules involved in BBB disruption and neuronal death.…”

Role of Neuron and Glia in Alzheimer’s Disease and Associated Vascular Dysfunction

“…The amyloid β (Aβ) plaques and hyperphosphorylated-tau-induced neurofibrillary tangles (NFTs) in the hippocampus and cortical region have long been considered as the only key pathological features of AD (Jacobs et al, 1992 ; Jellinger and Bancher, 1998 ). Nonetheless, over the years significant association of AD with vascular dysfunction has been reported, involving brain metabolic derangements, deregulated Aβ clearance, and a subsequent loss in neuronal homeostasis (Cortes-Canteli and Iadecola, 2020 ; He et al, 2020a ).…”

“…Both amyloid and vascular concepts are well-studied in AD. Specifically, there have been exploratory studies discerning the cumulative involvements of ROS, inflammation, NVU dysfunction, and changes in the brain microvasculature on AD pathogenesis (He et al, 2020a ; Ulamek-Koziol et al, 2020 ). However, a thorough understanding of the neuronal and vascular impairments, together with the participation of brain cells, in AD is yet awaited.…”

Common Protective Strategies in Neurodegenerative Disease: Focusing on Risk Factors to Target the Cellular Redox System

“…In particular, after TBI, many patients show motor and cognitive manifestations similar to those observed in AD and PD patients [ 10 – 12 ]. During the last century, a growing research interest has been addressed to the identification of mechanisms and risk factors leading to the complex etiopathogenesis of neurodegenerative diseases, including not only genetic, vascular, and metabolic but also lifestyle-related factors, which often coexist and interact with each other [ 13 – 15 ].…”