Accumulation of fibrillar amyloid b protein in blood vessels of the brain, a condition known as cerebral amyloid angiopathy (CAA), is a common pathology of elderly individuals, a prominent comorbidity of Alzheimer disease, and a driver of vascular cognitive impairment and dementia. Although several transgenic mouse strains have been generated that develop varying levels of CAA, consistent models of associated cerebral microhemorrhage and vasculopathy observed clinically have been lacking. Reliable preclinical animal models of CAA and microhemorrhage are needed to investigate the molecular pathogenesis of this condition. Herein, we describe the generation and characterization of a novel transgenic rat (rTg-DI) that produces low levels of human familial CAA Dutch/Iowa E22Q/D23N mutant amyloid b protein in brain and faithfully recapitulates many of the pathologic aspects of human smallvessel CAA. rTg-DI rats exhibit early-onset and progressive accumulation of cerebral microvascular fibrillar amyloid accompanied by early-onset and sustained behavioral deficits. Comparable to CAA in humans, the cerebral microvascular amyloid in rTg-DI rats causes capillary structural alterations, promotes prominent perivascular neuroinflammation, and produces consistent, robust microhemorrhages and small-vessel occlusions that are readily detected by magnetic resonance imaging. The rTg-DI rats provide a new model to investigate the pathogenesis of small-vessel CAA and microhemorrhages, to develop effective biomarkers for this condition and to test therapeutic interventions. (Am J Pathol 2018, 188: 2877e2889; https://doi.

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.

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.

Cerebral amyloid angiopathy (CAA) is the deposition of amyloid protein in the cerebral vasculature, a common feature in both aging and Alzheimer’s disease (AD). However, the effects of environmental factors, particularly cognitive stimulation, social stimulation, and physical activity, on CAA pathology are poorly understood. These factors, delivered in the form of the environmental enrichment (EE) paradigm in rodents, have been shown to have beneficial effects on the brain and behavior in healthy aging and AD models. However, the relative importance of these subcomponents on CAA pathology has not been investigated. Therefore, we assessed the effects of EE, social enrichment (SOC), and cognitive enrichment (COG) compared to a control group that was single housed without enrichment (SIN) from 4 to 8 months of age in wild-type mice (WT) and Tg-SwDI mice, a transgenic mouse model of CAA that exhibits cognitive/behavioral deficits. The results show that individual facets of enrichment can affect an animal model of CAA, though the SOC and combined EE conditions are generally the most effective at producing physiological, cognitive/behavioral, and neuropathological changes, adding to a growing literature supporting the benefits of lifestyle interventions.