Senescent Cells Contribute to Vascular Dysfunction and the Biochemistry of Alzheimer's Disease
Researchers here make an effort to link the age-related accumulation of senescent cells in vascular tissue with some of the better known biochemistry of Alzheimer's disease. Progressive vascular dysfunction is an important component of aging: loss of elasticity; failure to regulate blood pressure; failing constriction and dilation; the the corrosive growth of fatty atherosclerotic plaques that weaken and narrow blood vessels; increased amyloid deposition in blood vessel walls. In the brain particularly, failure to deliver sufficient oxygen and nutrients via the vascular system is a notable contributing factor in the onset of dementia, and a sizable fraction of Alzheimer's patients also exhibit full-blown vascular dementia.
Recent studies have suggested that senescent cells have a larger role in vascular aging than was previously assumed, contributing to most of the line items noted above, and this open access paper continues that theme. One of the more interesting points of focus here is the generation of amyloid-β, a protein that accumulates in Alzheimer's disease, in the vascular system, both inside and outside the brain. This appears to take place to a greater degree in senescent cells. It will be a most interesting new direction for Alzheimer's research should further investigations find that senescent cells are a significant source of amyloid. Given the low cost of senolytic drug candidates, someone should set up an exploratory trial.
Epidemiological, experimental, and clinical studies have suggested that age-related cerebrovascular dysfunction plays a critical role in the pathogenesis of dementia, including Alzheimer's disease (AD). Amyloid β (Aβ), the main constituent of amyloid plaques and a key pathogenic factor in AD, has detrimental effects on cerebral blood vessels resulting in disruption of homeostatic function of the cerebrovascular endothelial cells. The present study was designed to determine the effects of senescence and angiotensin II (Ang II) on expression and processing of amyloid precursor protein (APP) in human brain microvascular endothelial cells (BMECs).
Cellular senescence is an important contributor to aging and age-related diseases. Prior studies provided evidence that processing of endogenous APP is down-regulated in senescent human fibroblasts, but the effects of senescence on APP expression and processing in vascular endothelium have not been studied. APP is highly expressed in endothelium and can be processed by two major proteolytic pathways. In the non-amyloidogenic pathway, APP is cleaved by α-secretase thereby generating soluble APPα (sAPPα), a well-known anticoagulant, neurotrophic, and neuroprotective molecule. In contrast, amyloidogenic processing of APP sequentially driven by β-site APP cleaving enzyme (BACE1) and γ-secretase generates cytotoxic Aβ. Under pathological conditions, β-processing of APP is activated therefore increasing production of Aβ. Importantly, inhibition of BACE1 could prevent or reduce the accumulation of Aβ in the brain, thereby reducing AD-related pathology. Not surprisingly, inhibitors of BACE1 are currently being developed for the treatment of AD.
Taken together, the results of the present study suggest that reduced APP expression contributes to down-regulation of sAPPα in senescent brain microvascular endothelium. Increased BACE1 expression and Aβ production suggest that senescence promotes β-processing of APP. Treatment with a BACE1 inhibitor is beneficial for senescent human BMECs. This effect is mediated by shifting of APP processing towards non-amyloidogenic pathway. The present study also reports a novel observation regarding the detrimental effects of Ang II on α-processing of APP by activation of AT2R in senescent human BMECs. Given the fact that the cleavage products of APP play an important role in vascular homeostasis, we propose that increased Aβ production together with loss of sAPPα are previously unrecognized mechanisms of cerebral microvascular endothelial dysfunction induced by senescence and Ang II. Our findings support the concept that pathological expression and processing of APP in senescent cerebrovascular endothelium may play an important role in pathogenesis of cerebral amyloid angiopathy and AD.
The main source of APP protein in the blood stream are the platelets. When they get old and senescent, some researchers think they are the source of a lot of atherosclerotic plaque and amyloid beta that gets carried to the brain and then is involved with development of AD. My thought is that humans in general have way too high of a platelet count, and as people age, causes much of the clogging up and disease in the cardiovascular system. Taking a low dose aspiring helps reduce platelet counts and aggregation, so that could be somewhat of a help. My platelet count is 104K, while most people have two to three times that count. My low platelet count is due to my having Gilbert's Syndrome (an inherited genetic trait affecting about 5% of Caucasians), which greatly reduces platelet count and raises bilirubin (a very strong antioxidant the protects the endothelium) levels 2 to 3X over normal levels.
PS: By the way Gilbert's Syndrome has a 0.5 all cause mortality risk, as it is very protective of atherosclerosis and many other diseases, including dementia and cancer.
Thanks for the info on GS Biotechy. I have moderate GS, I average around 1.6 mg/dL. Here is a nice summary of studies on heart disease association I found http://www.atherosclerosis-journal.com/article/S0021-9150(08)00053-1/fulltext As far as platelets, mine run high normal, avg about 350, I can't find a study strongly correlating GS with lower platelets, at least not more than a 10% differential.
Veritas Genetics told me that GS results in about 40% lower platelet counts (mine is 104) than normal persons. On my visit to my wellness Dr. we discussed my low platelet number and he said the low count is normal and expected for those with GS. My latest bilirubin level was 2.2 mg/dL. I checked my genetics and found the 3 SNP's that confirm GS, but I am wondering if you had your genetics tested for it? Bilirubin can be high for other reasons than GS, and the reason I bring this up is because your platelet count is much, much higher than GS people are suppose to have.
PS: Thanks for the very thorough and informative article on GS and its protective effects on atherosclerosis.
@JohnD: Found a quick reference to reduced platelet counts with GS in the Wikipedia write up for the condition under the Cardiovascular effects section.