The influence of chromosome 4 on metabolism and spatial memory in SHR and SLA16 rat strains.

The Spontaneously Hypertensive Rat (SHR) has been proposed as a good model to study the pathways related to neurodegenerative diseases and glucose intolerance. Our research group developed the SLA16 (SHR.LEW-Anxrr16) congenic strain, which is genetically identical to the SHR strain, except for a locus on chromosome 4 (DGR). We applied in silico analysis on DGR to evaluate the association of their genes with neurobiological and metabolic pathways. After, we characterized cholesterol, triglycerides, metabolism of glucose and the behavioral performance of young (2 months old) and adult (8 months old) SHR and SLA16 rats in the open field, object location and water maze tasks. Finally, naïve young rats were repeatedly treated with metformin (200 mg/kg; v.o.) and evaluated in the same tests. Bioinformatics analysis showed that DGR presents genes related to glucose metabolism, oxidative damage and neurodegenerative diseases. Young SLA16 presented higher cholesterol, triglycerides, glucose and locomotion in the open field than SHR rats. In adulthood, SLA16 rats presented high triglycerides and locomotion in the open field and impairment on spatial learning and memory. Finally, the treatment with metformin decreased the glucose tolerance curve and also improved long-term memory in SLA16 rats. These results indicate that DGR presents genes associated with metabolic pathways and neurobiological processes that may produce alterations in glucose metabolism and spatial learning/memory. Therefore, we suggest that SHR and SLA16 strains could be important for the study of genes and subsequent mechanisms that produce metabolic glucose alterations and age-related cognitive deficits.

Hypercholesterolemia induces short-term spatial memory impairments in mice: up-regulation of acetylcholinesterase activity as an early and causal event?

Epidemiological studies have indicated hypercholesterolemia in midlife as a risk factor for dementia in later life, bringing cholesterol to the forefront of Alzheimer's disease research. Herein, we modeled mild hypercholesterolemia in mice to evaluate biochemical and behavioral alterations linked to hypercholesterolemia. Swiss mice were fed a high fat/cholesterol diet (20 % fat and 1.25 % cholesterol) for an 8-week period (from 12 to 18 weeks old) and were tested on the object location, forced swimming and elevated plus-maze tasks. We also investigated hypercholesterolemia-induced changes on acetylcholinesterase (AChE) activity, oxidative damage, amyloid precursor protein (APP) processing and blood brain barrier (BBB) integrity within the prefrontal cortex and hippocampus. It was found that increased AChE activity within the prefrontal cortex and hippocampus is an early event associated with hypercholesterolemia-induced short-term memory impairments. We observed no signs of antioxidant imbalance and/or oxidative damage or changes in cortical and hippocampal densities of beta-site amyloid precursor protein-cleaving enzyme 1 and aquaporin-4, biomarkers of APP processing and BBB integrity, respectively. In addition, we treated SH-SY5Y human neuroblastoma cells with low-density lipoprotein (LDL) cholesterol in an attempt to manipulate cell cholesterol content. Notably, LDL cholesterol increased in a dose-dependent manner the activity of AChE in SH-SY5Y cells. The present findings provide new evidence that increased AChE activity within the prefrontal cortex and hippocampus is an early event associated with hypercholesterolemia-induced cognitive impairments.

Folic acid plus α-tocopherol mitigates amyloid-ß-induced neurotoxicity through modulation of mitochondrial complexes activity.

Early symptoms of Alzheimer's disease (AD) have been attributed to amyloid-ß (Aß) toxicity. The pathophysiology of AD is complex and involves several different biochemical pathways, including defective Aß protein metabolism, neuroinflammation, oxidative processes, and mitochondrial dysfunction. In the current study, we assessed the molecular mechanisms, mainly the modifications in the activity of mitochondrial complexes, whereby the association of folic acid and α-tocopherol protects mice against the Aß-induced neurotoxicity. Oral treatment with folic acid (50 mg/kg) plus α-tocopherol (500 mg/kg), once a day during 14 consecutive days, protected mice against the Aß1₋40-induced cognitive decline, synaptic loss, and neuronal death. However, chronic treatment comprising folic acid plus α-tocopherol was ineffective on Aß-induced glial cell activation, suggesting that the effect of this treatment is independent of anti-inflammatory features. Interestingly, the results obtained in our study suggest that mitochondrial energy metabolism is impaired by the Aß peptide, and upregulation of mitochondrial genes may be a compensatory response, as demonstrated by the increase in mitochondrial complexes I, II, and IV activity, in the hippocampus of mice, after Aß1₋40 injection. Of note, the chronic treatment comprising folic acid plus α-tocopherol prevented the increase in the activity of mitochondrial complexes I and IV induced by Aß1₋40. Together, these results show the antioxidant effect of the combination of folic acid and α-tocopherol, as observed by the decrease in NO generation from iNOS and nNOS, preventing an increase in the activity of mitochondrial complexes, mainly I and IV, and the neuronal death induced by the Aß1₋40 peptide.

Environmental enrichment improves cognitive deficits in Spontaneously Hypertensive Rats (SHR): relevance for Attention Deficit/Hyperactivity Disorder (ADHD).

The interaction between genes and environment seems to be relevant for the development of Attention Deficit/Hyperactivity Disorder (ADHD), one of the most prevalent childhood psychiatric diseases. The occurrence of ADHD is typically associated with poor academic performance, probably reflecting learning difficulties and/or cognitive impulsiveness. The inbred Spontaneously Hypertensive Rats (SHR) strain has often been considered as an animal model of ADHD, since they 'naturally' display the main ADHD symptomatology. Although pharmacological agents improve SHR's cognitive deficits, little is known about the involvement of environmental factors in SHR disabilities and to what extent 'protective' non-pharmacological factors may be considered as strategy for ADHD prevention. Here we investigated whether the rearing environment during neurodevelopment may counteract later cognitive deficits presented by adult SHR. Wistar (WIS) rats were also used to investigate whether the putative effects of environmental enrichment depend on a specific genetic background. The animals were reared in enriched environment (EE) or standard environment (SE) from the post-natal day 21 until 3 months of age (adulthood) and tested for cognitive and non-cognitive phenotypes. EE improved SHR's performance in open field habituation, water maze spatial reference, social and object recognition tasks, while non-cognitive traits, such as nociception and hypertension, were not affected by EE. Response of WIS rats was generally not affected by the present EE. These results show that the general low cognitive performance presented by SHR rats strongly depends on the rearing environment and they may suggest modifications of the familial environment as a putative preventive strategy to cope with ADHD.