Anti-inflammatory effects of physical activity in relationship to improved cognitive status in humans and mouse models of Alzheimer's disease

Abstract

Physical activity has been correlated with a reduced incidence of cognitive decline and Alzheimer's disease in human populations. Although data from intervention-based randomized trials is scarce, there is some indication that exercise may confer protection against age-related deficits in cognitive function. Data from animal models suggests that exercise, in the form of voluntary wheel running, is associated with reduced amyloid deposition and enhanced clearance of amyloid beta, the major constituent of plaques in Alzheimer's disease. Treadmill exercise has also been shown to ameliorate the accumulation of phosphorylated tau, an essential component of neurofibrillary tangles in Alzheimer's models. A common therapeutic theme arising from studies of exercise-induced neuroprotection in human populations and in animal models involves reduced inflammation in the central nervous system. In this respect, physical activity may promote neuronal resilience by reducing inflammation.

Figures

Figure 1. Changes in amyloid precursor protein processing, plaque accumulation, and tau phosphorylation with increased physical activity

(A), Voluntary wheel running reduces amyloid precursor protein mRNA [7], and reduces levels of the alpha and beta C-terminal fragments [8]. Physical activity also reduces the ratio of Aβ1–40 to Aβ1–42 [8, 15, 36]. Lastly, running has been associated with reduced plaque burden in some [8, 34], but not all [7, 26, 31] studies. (B), Transgenic mice expressing human tau exhibit reduced phosphorylation of phosphoinositol-3 kinase (PI3K); physical activity reverses this effect [9]. Similarly, transgenic mice expressing human tau show reduced phosphorylation of Akt, and exercise reinstates Akt phosphoryaltion [9]. Phosphorylation of PI3K/Akt inhibits phosphorylation of glycogen synthase kinase-3β (GSK3β), which in turn phosphorylates tau. In keeping with this relationship, transgenic mice exhibit increased phosphorylation of GSK3β and tau. Treadmill running reversed the increase in phosphorylation of GSK3β and tau [9].