Involvement of cerebrovascular abnormalities in the pathogenesis and progression of Alzheimer’s disease: an adrenergic approach

Abstract

Alzheimer’s disease (AD), as the most common neurodegenerative disease in elder population, is pathologically characterized by β-amyloid (Aβ) plaques, neurofibrillary tangles composed of highly-phosphorylated tau protein and consequently progressive neurodegeneration. However, both Aβ and tau fails to cover the whole pathological process of AD, and most of the Aβ- or tau-based therapeutic strategies are all failed. Increasing lines of evidence from both clinical and preclinical studies have indicated that age-related cerebrovascular dysfunctions, including the changes in cerebrovascular microstructure, blood-brain barrier integrity, cerebrovascular reactivity and cerebral blood flow, accompany or even precede the development of AD-like pathologies. These findings may raise the possibility that cerebrovascular changes are likely pathogenic contributors to the onset and progression of AD. In this review, we provide an appraisal of the cerebrovascular alterations in AD and the relationship to cognitive impairment and AD pathologies. Moreover, the adrenergic mechanisms leading to cerebrovascular and AD pathologies were further discussed. The contributions of early cerebrovascular factors, especially through adrenergic mechanisms, should be considered and treasured in the diagnostic, preventative, and therapeutic approaches to address AD.

Cerebrovascular reactivity in Alzheimer's disease signature regions is associated with mild cognitive impairment in adults with hypertension

“…Although higher CVR in the AD signature regions that typically thin or atrophy throughout AD progression is associated with lower MCI risk, 24–26 regional volumes other than the hippocampus were not associated with MCI risk, indicating that CVR changes may precede morphometric changes, consistent with other studies suggesting BBB breakdown and CBF dysregulation precede neurodegeneration 39,40 . These findings corroborate cross‐sectional human studies and rodent models, which correlate CVR reduction with AD progression 6–10,12–16,22,23 …”

“…39,40 These findings corroborate cross-sectional human studies and rodent models, which correlate CVR reduction with AD progression. [6][7][8][9][10][12][13][14][15][16]22,23 Human studies have shown that participants with MCI and dementia have lower CVR compared to cognitively unimpaired individuals. 23 among a cohort of younger subjects, indicating that CVR-related changes in cognition may be independent from the progression of AD-related pathologies.…”

The Protective Effects of Zeaxanthin on Amyloid-β Peptide 1–42-Induced Impairment of Learning and Memory Ability in Rats

“…Recent studies have shown that atherosclerosis ( Lin et al, 2022 ), cerebrovascular endothelial damage ( Xi et al, 2012 ), the Aβ clearance dysfunction ( Xi et al, 2013 ), the oxidative damage resulting in the blood–brain barrier (BBB) broken, and cerebral microvascular pathology ( Boese et al, 2020 ; Kurz et al, 2021 ; Owens et al, 2022 ) have a close relationship with the advancement of AD. These findings suggest that cerebrovascular dysfunction might be key pathogenesis in the development of AD ( Li et al, 2021 ). It is reported that oxidative damage is an important case in the progress of cerebrovascular pathology ( Chen et al, 2022 ; Martini et al, 2022 ).…”

Blood–Brain Barrier Breakdown in Alzheimer’s Disease: Mechanisms and Targeted Strategies

“…This decreased expression could contribute to an impaired efflux of neurotoxic substances and Aβ peptides, potentially exacerbating AD pathology [113]. Moreover, recent studies indicate that certain MRPs may be involved in clearing Aβ peptides from the brain, with the dysregulated MRP function potentially contributing to Aβ accumulation and neurotoxicity [15], given the potential connection between the MRP dysfunction and AD pathology.…”

“…In line with this, the two-hit vascular hypothesis of AD suggests cerebrovascular damage (hit 1) as an initial insult that is self-sufficient to initiate neuronal injury and neurodegeneration. Additionally, it promotes the buildup of Alzheimer's Aβ toxin in the brain (hit 2) [15].…”