Differential proteomic and behavioral effects of long-term voluntary exercise in wild-type and APP-overexpressing transgenics

Abstract

Physical exercise may provide protection against the cognitive decline and neuropathology associated with Alzheimer’s disease, although the mechanisms are not clear. In the present study, APP/PSEN1 double-transgenic and wild-type mice were allowed unlimited voluntary exercise for 7 months. Consistent with previous reports, wheel-running improved cognition in the double-transgenic mice. Interestingly, the average daily distance run was strongly correlated with spatial memory in the water maze in wild-type mice (r2 = .959), but uncorrelated in transgenics (r2 = .013). Proteomics analysis showed that sedentary transgenic mice differed significantly from sedentary wild-types with respect to proteins involved in synaptic transmission, cytoskeletal regulation, and neurogenesis. When given an opportunity to exercise, the transgenics’ deficiencies in cytoskeletal regulation and neurogenesis largely normalized, but abnormal synaptic proteins did not change. In contrast, exercise enhanced proteins associated with cytoskeletal regulation, oxidative phosphorylation, and synaptic transmission in wild-type mice. Soluble and insoluble Aβ40 and Aβ42 levels were significantly decreased in both cortex and hippocampus of active transgenics, suggesting that this may have played a role in the cognitive improvement in APP/PSEN1 mice. β-secretase was significantly reduced in active APP/PSEN1 mice compared to sedentary controls, suggesting a mechanism for reduced Aβ. Taken together, these data illustrate that exercise improves memory in wild-type and APP-overexpressing mice in fundamentally different ways.

Retroviral induction of GSK-3β expression blocks the stimulatory action of physical exercise on the maturation of newborn neurons

“…However, although it has been proposed that physical exercise protects against the development of AD [65], it remains unclear whether it is beneficial after the onset of the disease. Indeed, several studies suggest that exercise fails to increase neural plasticity in animal models and AD patients [67,68]. To demonstrate whether GSK-3b overexpression interferes with the stimulatory actions of physical exercise, we subjected the retrovirus-injected mice to a period of voluntary wheel running (Fig.…”

Environmental Enrichment as a Positive Behavioral Intervention Across the Lifespan

“…Interestingly, previous studies have found that the effects of EE in Alzheimer´s animal models were observed after complex enrichment (enriched environment plus exercise) but not after exercise alone [ 125 , 148 ]. However, a recent study [ 149 ] has found that voluntary exercise improved the memory performance in the APP/PSEN1 double-transgenic mouse model, although the amount of daily exercise was not correlated with spatial performance. As previously mentioned, EE is a stimulation protocol also involved in the recovery from different sorts of brain damage [ 150 ].…”

Shared Neuropathological Characteristics of Obesity, Type 2 Diabetes and Alzheimer’s Disease: Impacts on Cognitive Decline

“…One of the conclusions from the Maesako et al study [ 126 ] was that exercise improved memory in the MWM better than diet control. This seems reasonable given that exercise offers some of the same benefits as diet control, such as weight loss and decreased adiposity; however, unlike diet control exercise can also increase neurogenesis and improve cardiovascular health [ 131 ], and can induce changes in synaptic and cytoskeletal proteins to different extents in wildtype and AD mutant mice [ 132 ]. Furthermore, in rodents, even short-term (6 weeks) environmental enrichment, in the absence of physical activity, has been shown to improve spatial learning and working memory performance, in addition to increasing neurogenesis and synaptogenesis in the dentate gyrus [ 133 ].…”