The effect of age and obesity on platelet amyloid precursor protein processing and plasma markers of oxidative stress and inflammation.

Abstract

Advancing age is a major risk factor for a range of diseases such as, cardiovascular disease, diabetes, cancer and neurodegenerative diseases. In addition, over a third of the population are overweight and obesity is becoming more prevalent in younger people. Ageing and obesity are both linked to a chronic proinflammatory state and elevated oxidative stress, which have both been implicated in cardiovascular and neurodegenerative diseases. Platelets contain all the necessary machinery to process the Amyloid precursor protein AβPP, a pathway thought to be perturbed in Alzheimer's Disease (AD). The ratio of AβPP isoforms present in platelets, and the amount of alpha secretase ADAM10, that works to process AβPP, appear to be associated with cognitive decline and a diagnosis of Alzheimer's disease. The aim of this study was to assess changes in AβPP ratio, ADAM10 and markers of inflammation and oxidative stress with ageing and obesity. Ninety participants were recruited to this study to provide one blood sample. Platelet-rich plasma and platelet lysates were collected and the expression of AβPPr, proADAM10 and mADAM10 was assessed by Western blotting. In addition, markers of inflammation (IL-6) and oxidative stress (8-Isoprostane) were assessed in plasma. Participants were placed into one of four groups based on their age and body mass index (Young/Lean, Young/obese, Old/Lean and Old/Obese). IL-6 was able to significantly distinguish obese from lean participants (AUC of 0.80, SE=0.05, P<0.001). Plasma isoprostanes were able to distinguish between both young/old (AUC of 0.73, SE=0.05, P<0.01), and obese/non-obese participants (AUC of 0.66, SE=0.01, P<0.01). Plasma protein carbonyls could distinguish young and old participants (AUC of 0.69, SE=0.07 P<0.02). Old Lean participants had significantly lower mADAM10 expression than both Young Lean and Young Obese participants (p<0.05). Old obese participants had significantly lower proADAM10 expression compared to both Young Lean and Young Obese (p<0.05). Both mADAM10 and proADAM10 were significantly decreased with advancing age (p<0.05). The findings presented in this study provide evidence that blood-based biomarkers related to the pathology of AD are altered with age and obesity in otherwise healthy adults. Ageing was more strongly associated with elevated markers of oxidative stress whereas obesity was associated with elevated inflammatory IL-6.