Dissecting the Contribution of Vascular Alterations and Aging to Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive decline that afflicts as many as 45 % of individuals who survive past the age of 85. AD has been associated with neurovascular dysfunction and brain accumulation of amyloid-β peptide, as well as tau phosphorylation and neurodegeneration, but the pathogenesis of the disease is still somewhat unclear. According to the amyloid cascade hypothesis of AD, accumulation of amyloid-β peptide (Aβ) aggregates initiates a sequence of events leading to neuronal injury and loss, and dementia. Alternatively, the vascular hypothesis of AD incorporates the vascular contribution to the disease, stating that a primary insult to brain microcirculation (e.g., stroke) not only contributes to amyloidopathy but initiates a non-amyloidogenic pathway of vascular-mediated neuronal dysfunction and injury, which involves blood-brain barrier compromise, with increased permeability of blood vessels, leakage of blood-borne components into the brain, and, consequently, neurotoxicity. Vascular dysfunction also includes a diminished brain capillary flow, causing multiple focal ischemic or hypoxic microinjuries, diminished amyloid-β clearance, and formation of neurotoxic oligomers, which lead to neuronal dysfunction. Here we present and discuss relevant findings on the contribution of vascular alterations during aging to AD, with the hope that a better understanding of the players in the "orchestra" of neurodegeneration will be useful in developing therapies to modulate the "symphony".

Neurovascular unit impairment in early Alzheimer's disease measured with magnetic resonance imaging

“…Furthermore, upregulation of vasoconstrictors would by definition decrease local blood volume as was found in this study. The lower blood volume may be further explained by a lower vascular density which has also been found in AD (Janota et al, 2015).…”

“…Adding age as a confounder also did not change the correlation, which shows that increased BBB leakage due to age or partial volume effects caused by atrophy cannot explain the observed link between hypoperfusion and BBB leakage. Together, this all points toward a complicated progressive cascade of events that involves decreased CBF, BBB leakage and inflammation (Janota et al, 2015). Although the precise pathways remain to be elucidated, the correlation between hypoperfusion and increased BBB leakage does fit to the hypothesized positive feedback loop linking the BBB and M A N U S C R I P T…”

Gram-negative bacterial molecules associate with Alzheimer disease pathology

“…LPS and E coli K99 pili protein in vessels and ependymal cells could contribute to vessel injury 29 and ependymal injury 17 and WM injury observed in AD brains. There was more K99 pili protein in GM and WM of AD brains, and both WM and GM are consistently damaged in AD.…”

Aging of cerebral white matter

“…Indeed, disruptions in cholinergic neurotransmission are known to exacerbate cognitive impairments in pre-clinical AD (Lim et al, 2015). Compared to age-matched control subjects, AD patients exhibited greater blood brain barrier disruption (Erickson and Banks, 2013) and elevated expression of receptor for advanced glycation endproducts (RAGE) (Janota et al, 2016), which is essential for the influx of peripheral Aβ into the brain. Decreased expression of the efflux receptor for Aβ, lipoprotein receptor-related protein (LRP)-1 and increased influx receptor RAGE (Silverberg et al, 2010a; Silverberg et al, 2010b) has been reported in AD brains, which would be expected to enhance intracellular accumulation Aβ.…”