Normal aging is associated with chronic oxidative stress. In the basal ganglia, oxidative stress may contribute to the increased risk of Parkinson's disease in the elderly. Neurons are thought to actively utilize compensatory defense mechanisms, such as heat shock proteins (HSPs), to protect from persisting stress. Despite their protective role, little is known about HSP expression in the aging basal ganglia. The purpose of this study was to examine HSP expression in striatum, substantia nigra, globus pallidus and cortex in 6-, 18- and 30-month-old Fischer 344/Brown Norway rats. We found robust age-related increases in phosphorylated and total HSP25 in each brain region studied. Conversely, HSP72 (the inducible form of HSP70) was reduced with age, but only in the striatum. p38 MAPK, a protein implicated in activating HSP25, did not change with age, nor did HSC70 (the constitutive form of HSP70), or HSP60. These results suggest that HSP25 is especially responsive to age-related stress in the basal ganglia.
Amyloid-ß(Aß) aggregates are presumed to be found in the brain at an early stage of Alzheimer's disease (AD) but have seldom been assessed by brain biopsy during life in often elderly patients.
Between 1991 and 2006 we evaluated 468 patients with suspected normal pressure hydrocephalus with intraventricular pressure monitoring and a right frontal cortical biopsy sample immunostained for Aß and hyperphosphorylated tau (HPt). Adequate samples and the clinical follow-up data until death or the end of 2008, available in 433 cases, were reviewed for the clinical signs of dementia, including AD. Logistic regression analysis was used to analyze whether Aß and/or HPt in the biopsy samples obtained during life predicted development of cognitive impairment, in particular, AD.
Of the 433 frontal cortical samples, 42 (10%) displayed both Aß and HPt, 144 (33%) Aß only, and 247 (57%) neither Aß nor HPt. In a median follow-up time of 4.4 years, 94 patients (22%) developed clinical AD. The presence of both Aß and HPt was strongly associated (odds ratio [OR], 68.2; 95% confidence interval [CI], 22.1-210) and Aß alone significantly associated (OR, 10.8; 95% CI, 4.9-23.8) with the clinical diagnosis of AD.
This is the largest follow-up study of patients assessed for the presence of Aß and HPt in frontal cortical brain biopsy samples. 1) The presence of Aß and HPt spoke strongly for the presence or later development of clinical AD; 2) Aß alone was suggestive of AD; and 3) the absence of Aß and HPt spoke against a later clinical diagnosis of AD.
The serum anticholinergic activity (SAA) assay has been used to quantify patients' anticholinergic load. In addition, several ranked lists of anticholinergic drugs have been developed to assess anticholinergic drug burden.
This study investigated whether SAA assay results and scores from three ranked lists of anticholinergic drugs (Carnahan's Anticholinergic Drug Scale, Rudolph's Anticholinergic Risk Scale, and Chew's list) are associated with anticholinergic adverse drug events (ADEs) in older people.
We analyzed data from participants in the population-based Geriatric Multidisciplinary Good Care of the Elderly Study in Kuopio, Finland (n = 621). Demographic, diagnostic, and drug use data were collected during standardized interviews and verified from medical records. Vision, functional capacity, cognition, and mood were assessed using validated techniques. The SAA was measured from blood samples.
The SAA was not associated with anticholinergic ADEs. Anticholinergic drug burden computed using each of the three lists was inversely associated with short-distance vision (p
Cortical and cerebrovascular amyloid-? (A?) deposition is a hallmark of Alzheimer's disease (AD), but also occurs in elderly people not affected by dementia. The apolipoprotein E (APOE) e4 is a major genetic modulator of A? deposition and AD risk. Variants of the amyloid-? protein precursor (A?PP) gene have been reported to contribute to AD and cerebral amyloid angiopathy (CAA). We analyzed the role of APOE and A?PP variants in cortical and cerebrovascular A? deposition, and neuropathologically verified AD (based on modified NIA-RI criteria) in a population-based autopsy sample of Finns aged = 85 years (Vantaa85 + Study; n = 282). Our updated analysis of APOE showed strong associations of the e4 allele with cortical (p = 4.91 ? 10-17) and cerebrovascular (p = 9.87 ? 10-11) A? deposition as well as with NIA-RI AD (p = 1.62 ? 10-8). We also analyzed 60 single nucleotide polymorphisms (SNPs) at the A?PP locus. In single SNP or haplotype analyses there were no statistically significant A?PP locus associations with cortical or cerebrovascular A? deposition or with NIA-RI AD. We sequenced the promoter of the A?PP gene in 40 subjects with very high A? deposition, but none of these subjects had any of the previously reported or novel AD-associated mutations. These results suggest that cortical and cerebrovascular A? depositions are useful quantitative traits for genetic studies, as highlighted by the strong associations with the APOE e4 variant. Promoter mutations or common allelic variation in the A?PP gene do not have a major contribution to cortical or cerebrovascular A? deposition, or very late-onset AD in this Finnish population based study.
Cites: Nat Genet. 2009 Oct;41(10):1088-9319734902
Cites: CNS Neurol Disord Drug Targets. 2009 Mar;8(1):16-3019275634
Thyroxine synthesis inhibitors increase the predisposition to catalepsy and decrease sexual motivation and the amplitude of the acoustic startle reflex in rats. The sensitivity of these behavioral changes to antidepressants remains uncertain. Chronic administration of the classical tricyclic antidepressant imipramine (15 mg/kg, 21 days) prevented the appearance of high sensitivity to catalepsy and the decrease in sexual motivation in Wistar rats given propylthiouracil (50 mg/liter, 28 days), without altering the amplitude of the startle reflex. Normalization of behavior in response to imipramine was not associated with changes in movement activity in the open field test or the animals' body weight. There was also no change in the expression of the 5-HT2A serotonin receptor gene in the frontal cortex. The model of propylthiouracilinduced catalepsy with reduced sexual motivation in rats has potential for studying the role of thyroid abnormalities in the development of depression and the mechanisms of action of antidepressants.
Duration of cataleptic reactions in male rats of Wistar and GC strains depended both on the genotype and on the type of rearing: it was longer in the GC rats than in the Wistar ones. In the GC males reared by Wistar foster mothers this parameter was smaller than in the control GC but higher than in Wistar rats. The NA content was significantly lower in the GC cortex, hypothalamus and striatum, and the level of serotonin and 5-HIAA was lower in cortex of the GC as compared with Wistar rats. The cross-fostering affected monoamine content in some brain structures. On the whole, serotonin, DA and NA systems of the GC rats proved to be more susceptible to stress caused by cross-fostering than those of the Wistar rats. The cross-fostering diminished interstrain differences in the NA level in cortex, striatum, and hypothalamus.
It has been proved that oxidative stress increases when leukemia is accompanied by depression. This fact may indicate the role of oxidative stress in the development of depression in cancer patients. The aim of this study was to determine whether the acute myeloid leukemia of Brown Norway rats, which is accompanied by oxidative stress, evoked behavioral and receptor changes resembling alterations characteristic of rat models of depression. The rats were divided into two groups: leukemic rats and healthy control. Leukemia was induced through intraperitoneal injection of 10(7) promyelocytic leukemia cells to the Brown Norway rats. Depression-like behavior was evaluated in the forced swim test at 30 or 34 days after leukemic cells injection. The rats were killed after the evaluation and the spleen, brain cortex and hippocampus were excised. The red-ox state was assessed in homogenates of tissues by measuring total glutathione (GSH) content, the ferric ion reducing ability of plasma (FRAP) level, expression of heme oxygenase-1 (HO-1), biliverdin reductase (BvR) and ferritin mRNA, superoxide dismutase (SOD) activity, as well as malondialdehyde (MDA) concentration. Radioligand binding assay was used to assess of the effect of leukemia on cortical receptors. Leukemic cells were identified using RM-124 antibody by FACS Calibur flow cytometry. Leukemia influenced locomotory activity as well as forced swim test behavior in a 34-day series of experiments. Signs of oxidative stress in leukemic rats were observed in each examined stage of leukemia development. The FRAP values and glutathione contents, were significantly lowered whereas HO-1 mRNA expression, and malonodialdehyde concentrations were significantly increased in the spleen and brain structures of leukemic rats in comparison with the healthy controls. A significant increase in the potency of glycine to displace [(3)H]L-689,560 from the strychnine-insensitive glycine site of the N-methyl-D-aspartic (NMDA) receptors receptor complex in cortical homogenates of the leukemic rats in 30- and 34-day experimental series was observed in comparison with the control. Upregulation of 5-HT(2A) receptors was observed in rat cortex after 30 days of leukemia development but not in 34-days series compared with the control. It is concluded that disturbances in antioxidant system in brain cortex were accompanied by an activation of glycine sites of the NMDA receptor complex, regardless of stage of leukemia development, which are characteristic of model of depression. Findings of our study demonstrate the link between glutamatergic activity, oxidative stress and leukemia.
Despite its estimated high heritability, the genetic architecture leading to differences in cognitive performance remains poorly understood. Different cortical regions play important roles in normal cognitive functioning and impairment. Recently, we reported on sets of regionally enriched genes in three different cortical areas (frontomedial, temporal and occipital cortices) of the adult rat brain. It has been suggested that genes preferentially, or specifically, expressed in one region or organ reflect functional specialisation. Employing a gene-based approach to the analysis, we used the regionally enriched cortical genes to mine a genome-wide association study (GWAS) of the Norwegian Cognitive NeuroGenetics (NCNG) sample of healthy adults for association to nine psychometric tests measures. In addition, we explored GWAS data sets for the serious psychiatric disorders schizophrenia (SCZ) (n = 3 samples) and bipolar affective disorder (BP) (n = 3 samples), to which cognitive impairment is linked.
At the single gene level, the temporal cortex enriched gene RAR-related orphan receptor B (RORB) showed the strongest overall association, namely to a test of verbal intelligence (Vocabulary, P = 7.7E-04). We also applied gene set enrichment analysis (GSEA) to test the candidate genes, as gene sets, for enrichment of association signal in the NCNG GWAS and in GWASs of BP and of SCZ. We found that genes differentially expressed in the temporal cortex showed a significant enrichment of association signal in a test measure of non-verbal intelligence (Reasoning) in the NCNG sample.
Our gene-based approach suggests that RORB could be involved in verbal intelligence differences, while the genes enriched in the temporal cortex might be important to intellectual functions as measured by a test of reasoning in the healthy population. These findings warrant further replication in independent samples on cognitive traits.
The effect of streptozotocin-induced diabetes on glial intermediate filament and behavioral reactions of rats was investigated. The water Morris test shows cognitive deficit in diabetic rats. The results of an immunoblot show both an increase in GFAP degradation and an increase in common GFAP amount in the brain of diabetic rats. The observations presented here suggest that diabetes induces the changes in activity of GFAP-positive glial cells. Such glial cells may be considered a key element in plasticity of nervous system. These results suggest that the impairment of learning and memory is accompanied by glial cytoskeletal reconstruction.
In recent years, transgenic mice have become valuable tools for studying mechanisms of Alzheimer's disease (AD). With the aim of developing an animal model better for memory and neurobehavioural testing, we have generated a transgenic rat model of AD. These animals express human amyloid precursor protein (APP) containing the Swedish AD mutation. The highest level of expression in the brain is found in the cortex, hippocampus, and cerebellum. Starting after the age of 15 months, the rats show increased tau phosphorylation and extracellular Abeta staining. The Abeta is found predominantly in cerebrovascular blood vessels with very rare diffuse plaques. We believe that crossing these animals with mutant PS1 transgenic rats will result in accelerated plaque formation similar to that seen in transgenic mice.