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

Abstract

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 (Aβ) 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 Aβ 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 Aβ 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 Aβ 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.

Environmental Enrichment: Disentangling the Influence of Novelty, Social, and Physical Activity on Cerebral Amyloid Angiopathy in a Transgenic Mouse Model

“…As in previous studies, we found that these increased levels of insoluble Aβ occurred in the presence of behavioral improvement and were therefore not detrimental to functioning, in agreement with previous findings that insoluble Aβ exhibits low toxicity [60][61][62]. Previously, we showed that exercise alone was also capable of dose-dependently increasing insoluble Aβ levels, despite some behavioral improvements and attenuated neuroinflammation [49]. Taken together, these findings suggest that enrichment factors increase the production/aggregation or reduce the degradation/clearance of Aβ, though vascular amyloid was specifically reduced in some brain regions.…”

“…As expected, the EE condition produced greater changes for some outcomes, such as muscle mass, tests of motor function and activity levels, and anxiety-like behavior, likely due to the addition of access to a running wheel to engage in voluntary aerobic exercise. Similarly, we previously reported the dose-dependent effects of aerobic exercise (voluntary wheel running) in WT mice and the Tg-SwDI model, with even relatively small amounts of exercise exerting notable benefits to physiology, motor function, anxiety, and cognition [49,50]. It should be noted that social and EE housing also reduced food intake and body weight in both WT and Tg-SwDI mice.…”

Voluntary running does not reduce neuroinflammation or improve non-cognitive behavior in the 5xFAD mouse model of Alzheimer’s disease

“…Although many experimental studies demonstrate reduced Aβ levels in the brain after exercise 39 , we could not detect any statistically significant changes on the levels of soluble Aβ 24 and insoluble Aβ. Interestingly, we observed a nonsignificant trend towards increased Aβ plaques in the hippocampus (p = 0.08) of running mice, in line with the effects of running found in a model of cerebral amyloid angiopathy 40 . In addition, other studies showed no effects of exercise on Aβ levels in mouse models of AD 41,42 .…”

Role of sex and high fat diet in metabolic and hypothalamic disturbances in the 3xTg-AD mouse model of Alzheimer’s disease

“…In agreement with this patient data, we saw no differences in caloric intake between 3xTg-AD and WT males. Other AD rodent models similarly report body weight deficits that become more pronounced with age, as well as decreased body fat, despite similar or even increased food consumption [24,[90][91][92][93][94]. While unclear in clinical populations, findings in mice exhibiting AD pathology suggest that elevated basal metabolic rate (measured by oxygen consumption), rather than increased activity levels, may be contributing to these differences [24,91,92,95].…”