Anaemia worsens early functional outcome after traumatic brain injury: a preliminary study.

OBJECTIVE: To determine early effects on outcome from traumatic brain injury (TBI) induced by controlled cortical impact (CCI) associated with anaemia in mice. HYPOTHESIS: Outcome from TBI with concomitant anaemia would be worse than TBI without anaemia. METHODS: CCI was induced with electromagnetic impaction in four groups of C57BL/6J mice: sham, sham+anaemia; TBI; and TBI+anaemia. Anaemia was created by withdrawal of 30% of calculated intravascular blood volume and saline replacement of equal volume. Functional outcome was assessed by beam-walking test and open field test (after pre-injury training) on post-injury days 3 and 7. After functional assessment, brains removed from sacrificed animals were pathological reviewed with haematoxylin and eosin, cresyl violet, Luxol Fast Blue, and IBA-1 immunostains. RESULTS: Beam-walking was similar between animals with TBI and TBI+anaemia (p = 0.9). In open field test, animals with TBI+anaemia walked less distance than TBI alone or sham animals on days 3 (p < 0.001) and 7 (p < 0.05), indicating less exploratory and locomotion behaviours. No specific pathologic differences could be identified. CONCLUSIONS: Anaemia associated with TBI from CCI is associated with worse outcome as measured by less distance travelled in the open field test at three days than if anaemia is not present.

Presenilin 1 transgene addition to amyloid precursor protein overexpressing transgenic rats increases amyloid beta 42 levels and results in loss of memory retention.

BACKGROUND: We previously reported the production of transgenic rats (APP21 line) that over-express human amyloid precursor protein (APP) containing Swedish and Indiana mutations. In order to generate a better model for Alzheimer's disease (AD), the APP21 rat line was used to generate double transgenic line that over-expressed Presenilin 1 (PS1) with L166P mutation in addition to APP transgene (APP + PS1 line). RESULTS: Thirty-two double transgenic founders were generated and the ultimate transgenic founder was selected based on PS1 transgene copy number and level of amyloid-beta (Aß)42 peptide. The APP + PS1 double transgenic rats had 38 times more PS1 in brains compared to APP rats. Behavioral assessment using Barnes maze showed that APP + PS1 rats exhibited a larger learning and memory deficit than APP21 rats. Double transgenic rats also produced more Aß42. Histological examination of the brains showed that the APP21 rat line displayed neurofibrillary tangles and in contrast, the APP + PS1 line showed chromatolysis in hippocampal neurons and neuronal loss in CA3 region of hippocampus. CONCLUSIONS: Due to the separate segregation of APP and PS1 transgenes in APP + PS1 double transgenic rats, this transgenic line may be a valuable model for studying the effects of various levels of APP and PS1 transgenes on various aspects of brain pathologies associated with the AD phenotype.

Ovariectomy Influences Cognition and Markers of Alzheimer's Disease.

Alzheimer's disease (AD) is one of the most devastating and costly diseases, and prevalence of AD increases with age. Furthermore, females are twice as likely to suffer from AD compared to males. The cessation of reproductive steroid hormone production during menopause is hypothesized to cause this difference. Two rodent AD models, APP21 and APP+PS1, and wild type (WT) rats underwent an ovariectomy or sham surgery. Changes in learning and memory, brain histology, amyloid-ß (Aß) deposition, levels of mRNAs involved in Aß production and clearance, and synaptic and cognitive function were determined. Barnes maze results showed that regardless of ovariectomy status, APP+PS1 rats learned slower and had poor memory retention. Ovariectomy caused learning impairment only in the APP21 rats. High levels of Aß42 and very low levels of Aß40 were observed in the brain cortices of APP+PS1 rats indicating limited endogenous PS1. The APP+PS1 rats had 43-fold greater formic acid soluble Aß42 than Aß40 at 17 months. Furthermore, levels of formic acid soluble Aß42 increased 57-fold in ovariectomized APP+PS1 rats between 12 and 17 months of age. The mRNA encoding Grin1 significantly decreased due to ovariectomy whereas levels of Bace1, Chat, and Prkcb all decreased with age. The expression levels of mRNAs involved in Aß degradation and AßPP cleavage (Neprilysin, Ide, Adam9, and Psenen) were found to be highly correlated with each other as well as hippocampal Aß deposition. Taken together, these results indicate that both ovariectomy and genotype influence AD markers in a complex manner.

Memory deficiency, cerebral amyloid angiopathy, and amyloid-ß plaques in APP+PS1 double transgenic rat model of Alzheimer's disease.

Transgenic rat models of Alzheimer's disease were used to examine differences in memory and brain histology. Double transgenic female rats (APP+PS1) over-expressing human amyloid precursor protein (APP) and presenilin 1 (PS1) and single transgenic rats (APP21) over-expressing human APP were compared with wild type Fischer rats (WT). The Barnes maze assessed learning and memory and showed that both APP21 and APP+PS1 rats made significantly more errors than the WT rats during the acquisition phase, signifying slower learning. Additionally, the APP+PS1 rats made significantly more errors following a retention interval, indicating impaired memory compared to both the APP21 and WT rats. Immunohistochemistry using an antibody against amyloid-ß (Aß) showed extensive and mostly diffuse Aß plaques in the hippocampus and dense plaques that contained tau in the cortex of the brains of the APP+PS1 rats. Furthermore, the APP+PS1 rats also showed vascular changes, including cerebral amyloid angiopathy with extensive Aß deposits in cortical and leptomeningeal blood vessel walls and venous collagenosis. In addition to the Aß accumulation observed in arterial, venous, and capillary walls, APP+PS1 rats also displayed enlarged blood vessels and perivascular space. Overall, the brain histopathology and behavioral assessment showed that the APP+PS1 rats demonstrated behavioral characteristics and vascular changes similar to those commonly observed in patients with Alzheimer's disease.

A chronic physical activity treatment in obese rats normalizes the contributions of ET-1 and NO to insulin-mediated posterior cerebral artery vasodilation.

This study tested the hypotheses that obesity-induced decrements in insulin-stimulated cerebrovascular vasodilation would be normalized with acute endothelin-1a receptor antagonism and that treatment with a physical activity intervention restores vasoreactivity to insulin through augmented nitric oxide synthase (NOS)-dependent dilation. Otsuka Long-Evans Tokushima Fatty rats were divided into the following groups: 20 wk old food controlled (CON-20); 20 wk old free food access (model of obesity, OB-20); 40 wk old food controlled (CON-40); 40 wk old free food access (OB-40); and 40 wk old free food access+RUN (RUN-40; wheel-running access from 20 to 40 wk). Rats underwent Barnes maze testing and a euglycemic hyperinsulinemic clamp (EHC). In the 40-wk cohort, cerebellum and hippocampus blood flow (BF) were examined (microsphere infusion). Vasomotor responses (pressurized myography) to insulin were assessed in untreated, endothelin-1a receptor antagonism, and NOS inhibition conditions in posterior cerebral arteries. Insulin-stimulated vasodilation was attenuated in the OB vs. CON and RUN groups (P ≤ 0.04). Dilation to insulin was normalized with endothelin-1a receptor antagonism in the OB groups (between groups, P ≥ 0.56), and insulin-stimulated NOS-mediated dilation was greater in the RUN-40 vs. OB-40 group (P < 0.01). At 40 wk of age, cerebellum BF decreased during EHC in the OB-40 group (P = 0.02) but not CON or RUN groups (P ≥ 0.36). Barnes maze testing revealed increased entry errors and latencies in the RUN-40 vs. CON and OB groups (P < 0.01). These findings indicate that obesity-induced impairments in vasoreactivity to insulin involve increased endothelin-1 and decreased nitric oxide signaling. Chronic spontaneous physical activity, initiated after disease onset, reversed impaired vasodilation to insulin and decreased Barnes maze performance, possibly because of increased exploratory behavior.NEW & NOTEWORTHY The new and noteworthy findings are that 1) in rodents, obesity-related deficits in insulin-mediated vasodilation are associated with increased influence of insulin-stimulated ET-1 and depressed influence of insulin-stimulated NOS and 2) a physical activity intervention, initiated after the onset of disease, restores insulin-mediated vasodilation, likely by normalizing insulin-stimulated ET-1 and NOS balance. These data demonstrate that the treatment effects of chronic exercise on insulin-mediated vasodilation extend beyond active skeletal muscle vasculature and include the cerebrovasculature.

Carotid Artery Vascular Mechanics Serve as Biomarkers of Cognitive Dysfunction in Aortic-Banded Miniature Swine That Can Be Treated With an Exercise Intervention.

BACKGROUND: Cognitive impairment in the setting of heart failure with preserved ejection fraction remains poorly understood. Using aortic-banded miniature swine displaying pathological features of human heart failure with preserved ejection fraction, we tested the hypothesis that increased carotid artery stiffness and altered carotid blood flow control are associated with impaired memory independent of decreased cardiac output. Furthermore, we hypothesized that chronic exercise prevents carotid artery vascular restructuring and preserves normal blood flow control and cognition in heart failure with preserved ejection fraction. METHODS AND RESULTS: Yucatan pigs aged 8 months were divided into 3 groups: control (n=7), aortic-banded sedentary (n=7), and aortic-banded exercise trained (n=7). At 6 months following aortic-banded or control conditions, memory was evaluated using a spatial hole-board task. Carotid artery vascular mechanics and blood flow were assessed at rest, and blood flow control was examined during transient vena cava occlusion. Independent of decreased cardiac output, the aortic-banded group exhibited impaired memory that was associated with carotid artery vascular stiffening, elevated carotid artery vascular resistance, and exaggerated reductions in carotid artery blood flow during vena cava occlusion. Chronic exercise augmented memory scores, normalized blood flow control, and improved indices of carotid artery vascular stiffening. Indices of vascular stiffening were significantly correlated with average memory score. CONCLUSIONS: Carotid artery stiffness and altered vasomotor control correlate with impaired cognition independent of cardiac systolic dysfunction. Carotid artery vascular mechanics may serve as a biomarker for vascular cognitive impairment in heart failure with preserved ejection fraction. Chronic low-intensity exercise reduces vascular stiffening and improves cognition, highlighting the utility of exercise therapy for treating vascular cognitive impairment in heart failure with preserved ejection fraction.

Beneficial effects of dietary EGCG and voluntary exercise on behavior in an Alzheimer's disease mouse model.

Alzheimer's disease (AD) is a progressive, age-dependent neurodegenerative disorder affecting specific brain regions that control memory and cognitive functions. Epidemiological studies suggest that exercise and dietary antioxidants are beneficial in reducing AD risk. To date, botanical flavonoids are consistently associated with the prevention of age-related diseases. The present study investigated the effects of 4 months of wheel-running exercise, initiated at 2-months of age, in conjunction with the effects of the green tea catechin (-)-epigallocatechin-3-gallate (EGCG) administered orally in the drinking water (50 mg/kg daily) on: (1) behavioral measures: learning and memory performance in the Barnes maze, nest building, open-field, anxiety in the light-dark box; and (2) soluble amyloid-ß (Aß) levels in the cortex and hippocampus in TgCRND8 (Tg) mice. Untreated Tg mice showed hyperactivity, relatively poor nest building behaviors, and deficits in spatial learning in the Barnes maze. Both EGCG and voluntary exercise, separately and in combination, were able to attenuate nest building and Barnes maze performance deficits. Additionally, these interventions lowered soluble Aß1-42 levels in the cortex and hippocampus. These results, together with epidemiological and clinical studies in humans, suggest that dietary polyphenols and exercise may have beneficial effects on brain health and slow the progression of AD.