Long-term voluntary wheel running does not alter vascular amyloid burden but reduces neuroinflammation in the Tg-SwDI mouse model of cerebral amyloid angiopathy.

BACKGROUND: Cardiovascular exercise (CVE) has been shown to be protective against cognitive decline in aging and the risk for dementias, including Alzheimer's Disease (AD). CVE has also been shown to have several beneficial effects on brain pathology and behavioral impairments in mouse models of AD; however, no studies have specifically examined the effects of CVE on cerebral amyloid angiopathy (CAA), which is the accumulation of amyloid-beta (Aß) in the cerebral vasculature. CAA may be uniquely susceptible to beneficial effects of CVE interventions due to the location and nature of the pathology. Alternatively, CVE may exacerbate CAA pathology, due to added stress on already compromised cerebral vasculature. METHODS: In the current study, we examined the effects of CVE over many months in mice, thereby modeling a lifelong commitment to CVE in humans. We assessed this voluntary CVE in Tg-SwDI mice, a transgenic mouse model of CAA that exhibits behavioral deficits, fibrillar vascular Aß pathology, and significant perivascular neuroinflammation. Various "doses" of exercise intervention (0 h ("Sedentary"), 1 h, 3 h, 12 h access to running wheel) were assessed from ~ 4 to 12 months of age for effects on physiology, behavior/cognitive performance, and pathology. RESULTS: The 12 h group performed the greatest volume of exercise, whereas the 1 h and 3 h groups showed high levels of exercise intensity, as defined by more frequent and longer duration running bouts. Tg-SwDI mice exhibited significant cerebral vascular Aß pathology and increased expression of pro-inflammatory cytokines as compared to WT controls. Tg-SwDI mice did not show motor dysfunction or altered levels of anxiety or sociability compared to WT controls, though Tg-SwDI animals did appear to exhibit a reduced tendency to explore novel environments. At all running levels, CAA pathology in Tg-SwDI mice was not significantly altered, but 12-h high-volume exercise showed increased insoluble Aß burden. However, CVE attenuated the expression of pro-inflammatory cytokines TNF-α and IL-6 and was generally effective at enhancing motor function and reducing anxiety-like behavior in Tg-SwDI mice, though alterations in learning and memory tasks were varied. CONCLUSIONS: Taken together, these results suggest that CAA can still develop regardless of a lifespan of substantial CVE, although downstream effects on neuroinflammation may be reduced and functional outcomes improved.

The effects of volume versus intensity of long-term voluntary exercise on physiology and behavior in C57/Bl6 mice.

Cardiovascular exercise (CVE) is associated with healthy aging and reduced risk of disease in humans, with similar benefits seen in animals. Most rodent studies, however, have used shorter intervention periods of a few weeks to a few months, begging questions as to the effects of longer-term, or even life-long, exercise. Additionally, most animal studies have utilized a single exercise treatment group - usually unlimited running wheel access - resulting in large volumes of exercise that are not clinically relevant. It is therefore incumbent to determine the physiological and cognitive/behavioral effects of a range of exercise intensities and volumes over a long-term period that model a lifelong commitment to CVE. In the current study, C57/Bl6 mice remained sedentary or were allowed either 1, 3, or 12 h of access to a running wheel per day, 5 days/weeks, beginning at 3.5-4 months of age. Following an eight-month intervention period, animals underwent a battery of behavioral testing, then euthanized and blood and tissue were collected. Longer access to a running wheel resulted in greater volume and higher running speed, but more breaks in running. All exercise groups showed similarly reduced body weight, increased muscle mass, improved motor function on the rotarod, and reduced anxiety in the open field. While all exercise groups showed increased food intake, this was greatest in the 12 h group but did not differ between 1 h and 3 h mice. While exercise dose-dependently increased working memory performance in the y-maze, the 1 h and 12 h groups showed the largest changes in the mass of many organs, as well as alterations in several behaviors including social interaction, novel object recognition, and Barnes maze performance. These findings suggest that long-term exercise has widespread effects on physiology, behavior, and cognition, which vary by "dose" and measure, and that even relatively small amounts of daily exercise can provide benefits.