Physiological variables.

<p>Values are mean ± SEM.</p><p>MCAo, middle cerebral artery occlusion.</p><p>MABP, mean arterial blood pressure.</p>*<p>different from saline group (p<0.05, Student’s t-test).</p

Computer-generated MosaiX-processed images of Nissl stained paraffin-embedded brain sections from rats treated with saline, DHA, Alb (0.63 and 1.25 g/kg) and DHA-Alb (0.63 and 1.25 g/kg) on day 3 after stroke.

<p>Saline- and both Alb-treated animals show large cortical and subcortical infarction. DHA-Alb- (0.63 g/kg) and DHA-treated rats showed moderate infarct involving cortical and subcortical regions. In contrast, rats treated with DHA-Alb (1.25 g/kg) showed less extensive damage, mostly in the subcortical area.</p

Histopathology on day 3 of survival.

<p>Cortical, subcortical and total integrated infarct areas and volumes in rats after permanent MCAo. Treatment with both doses of DHA-Alb reduced cortical, subcortical and total infarct volumes when treatment was administered at 3 h after onset of MCAo. Data are mean ± SEM. ^#<i>P</i><0.05 versus saline group; *<i>P</i><0.05 versus Alb (0.63 or 1.25 g/kg) groups (repeated-measures ANOVA followed by Bonferroni tests).</p

Total neurological score (normal score = 0, maximal score = 12) during MCAo (60 min) and on days 1, 2 and 3 after treatment.

<p>Treatment with DHA-Alb significantly improved neurological scores at 48 and 72 h. Values shown are means ± SEM. ^#<i>P</i><0.05 versus saline group; *<i>P</i><0.05 versus Alb (0.63 or 1.25 g/kg) groups (two-way repeated-measures ANOVA).</p

Data_Sheet_1_Cortical cerebrovascular and metabolic perturbations in the 5xFAD mouse model of Alzheimer’s disease.docx

IntroductionThe 5xFAD mouse is a popular model of familial Alzheimer’s disease (AD) that is characterized by early beta-amyloid (Aβ) deposition and cognitive decrements. Despite numerous studies, the 5xFAD mouse has not been comprehensively phenotyped for vascular and metabolic perturbations over its lifespan.MethodsMale and female 5xFAD and wild type (WT) littermates underwent in vivo18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging at 4, 6, and 12 months of age to assess regional glucose metabolism. A separate cohort of mice (4, 8, 12 months) underwent “vessel painting” which labels all cerebral vessels and were analyzed for vascular characteristics such as vessel density, junction density, vessel length, network complexity, number of collaterals, and vessel diameter.ResultsWith increasing age, vessels on the cortical surface in both 5xFAD and WT mice showed increased vessel length, vessel and junction densities. The number of collateral vessels between the middle cerebral artery (MCA) and the anterior and posterior cerebral arteries decreased with age but collateral diameters were significantly increased only in 5xFAD mice. MCA total vessel length and junction density were decreased in 5xFAD mice compared to WT at 4 months. Analysis of 18F-FDG cortical uptake revealed significant differences between WT and 5xFAD mice spanning 4–12 months. Broadly, 5xFAD males had significantly increased 18F-FDG uptake at 12 months compared to WT mice. In most cortical regions, female 5xFAD mice had reduced 18F-FDG uptake compared to WT across their lifespan.DiscussionWhile the 5xFAD mouse exhibits AD-like cognitive deficits as early as 4 months of age that are associated with increasing Aβ deposition, we only found significant differences in cortical vascular features in males, not in females. Interestingly, 5xFAD male and female mice exhibited opposite effects in 18F-FDG uptake. The MCA supplies blood to large portions of the somatosensory cortex and portions of motor and visual cortex and increased vessel length alongside decreased collaterals which coincided with higher metabolic rates in 5xFAD mice. Thus, a potential mismatch between metabolic demand and vascular delivery of nutrients in the face of increasing Aβ deposition could contribute to the progressive cognitive deficits seen in the 5xFAD mouse model.</p