Variants of the angiotensin I converting enzyme (peptidyl-dipeptidase A) 1 (ACE1) gene and the apolipoprotein E gene (APOE) have been suggested to be associated with human longevity. We tested the association between the ACE1 insertion (I allele)/deletion (D allele) polymorphism and longevity in a population from Southern Italy and examined the impact of geographical variation on ACE1 allele frequencies on reported associations from other European countries. ACE1 and APOE genotypes were obtained on 82 centenarians and 252 middle-aged, unrelated subjects or volunteers.
View Article and Find Full Text PDFJ Renin Angiotensin Aldosterone Syst
June 2003
Epidemiological studies from the last decade have begun to produce evidence that the perceived joint occurrence of vascular disease and Alzheimer's disease (AD), both common elderly disorders more often believed to occur by chance due to their high prevalence, may now actually have a more pathological significance. The following review discusses some of this evidence and the implications for cognitive decline and the development of AD and how a well-known cardiovascular risk factor gene, the apolipoprotein E (APOE) gene, plays a significant role in the molecular genetics of AD. It also introduces and discusses recent and compelling evidence for the involvement of another well-known cardiovascular risk factor gene, the angiotensin-converting enzyme (ACE1) gene, in the pathogenesis of AD.
View Article and Find Full Text PDFNumerous genes have been implicated in Alzheimer's disease (AD), but, with the exception of a demonstrated association with the epsilon 4 allele of APOE, findings have not been consistently replicated across populations. One of the most widely studied is the gene for angiotensin I converting enzyme (ACE ). A meta-analysis of published data on a common Alu indel polymorphism in ACE was performed which indicated highly significant association of the insertion allele with AD (OR 1.
View Article and Find Full Text PDFCocaine-induced increases in ventral striatal dopamine levels are enhanced in adult rats previously exposed to chronic stress. In neonatal rats, isolation from dam, nest, and siblings is stressful as evidenced by elevated corticosterone levels, an effect that increases with chronic isolation. Whether chronic neonatal isolation cross-sensitizes to cocaine leading to greater increases in ventral striatal dopamine levels was assessed in this study.
View Article and Find Full Text PDFRat pups were individually isolated from the mother and nest for 1 h/day from postnatal days (PND) 2 to 9 and tested as juveniles (PND 26-30) compared to nonhandled (NH) controls. In response to 1 h of restraint stress, NH rats increased locomotor activity and dopamine (DA) levels, but neonatally isolated (ISO) rats did not. Both groups had increased plasma corticosterone levels in response to restraint, but corticosterone levels were higher in ISO than in NH.
View Article and Find Full Text PDFWe performed a two-stage genome screen to search for novel risk factors for late-onset Alzheimer disease (AD). The first stage involved genotyping 292 affected sibling pairs using 237 markers spaced at approximately 20 cM intervals throughout the genome. In the second stage, we genotyped 451 affected sibling pairs (ASPs) with an additional 91 markers, in the 16 regions where the multipoint LOD score was greater than 1 in stage I.
View Article and Find Full Text PDFBrain Res Dev Brain Res
December 2001
Maturation of the nervous system and consequent behavior depends in part on prenatal nutritional factors and postnatal environmental stimulation. In particular, the hypothalamus and the hippocampus are two important CNS areas that are vulnerable to such pre- and postnatal manipulations. Therefore, the present study was undertaken to explore the effects of both prenatal protein malnutrition and neonatal isolation stress on hypothalamic and hippocampal functioning in infant rats.
View Article and Find Full Text PDFThe induction of long-term potentiation (LTP) within the dentate gyrus of the hippocampal formation is modulated by many afferent influences from a number of subcortical structures known to be intimately involved in hippocampal-dependent learning and memory. It has been demonstrated in slice and anesthetized preparations that norepinephrine (NE) is one of these major neuromodulators involved in the induction of LTP. However, the majority of these studies have not been conducted in the freely moving animal.
View Article and Find Full Text PDFEarly life events have been thought to contribute towards vulnerability to drug addiction later in life. In the present investigation, the effect of daily neonatal maternal isolation stress on NMDA channel activity was studied. [3H]MK-801 binding was measured in several brain regions from neonatally isolated (ISO) and nonhandled (NH) adult male and female rats.
View Article and Find Full Text PDFAs cholinergic stimulation increases vocalizations in adult rats, the present study investigated the effects of systemic oxotremorine, a cholinergic agonist, on the production of separation calls in rat pups of different ages and whether these effects are in response to central versus peripheral stimulation. The first experiment examined the dose-response effects of oxotremorine on the number of vocalizations and acoustic parameters of 10-, 15-, and 17-day-old rat pups. In contrast to other studies on adult rats, pup vocalizations were decreased while marginally changing acoustic parameters.
View Article and Find Full Text PDFBackground: Alzheimer's disease manifests considerable heterogeneity, the cause of which is unknown.
Aims: To determine the familial (genotypic) influence on phenomenology (phenotype) in Alzheimer's disease.
Method: Affected sibling pairs with Alzheimer's disease were assessed for a range of cognitive and non-cognitive symptoms.
The apolipoprotein E (APOE) gene is the only genetic risk factor that has so far been linked to risk for late-onset Alzheimer's disease (LOAD). However, 50 percent of Alzheimer's disease cases do not carry an APOE4 allele, suggesting that other risk factors must exist. We performed a two-stage genome-wide screen in sibling pairs with LOAD to detect other susceptibility loci.
View Article and Find Full Text PDFBrain Res Dev Brain Res
November 2000
This experiment investigated whether neonatal isolation stress alters central concentrations of progestins. Whole brain progesterone (P), dihydroprogesterone (DHP), and allopregnanolone (3alpha, 5alpha-THP) were measured in pups that were isolated from the nest, dam, and siblings for 1 h on postnatal days (PND) 2-9 and were compared to control litters of pups that were not isolated. Isolated 2-day-old pups had significantly lower central P and higher P to DHP and 3alpha, 5alpha-THP metabolism ratios.
View Article and Find Full Text PDFThat stress enhances the behavioral effects of cocaine is well-documented in adult rats, but whether early life stress endures into adulthood to affect responsivity to cocaine is less clear. We now report that neonatal isolation stress (1 h per day isolation on postnatal days 2-9) enhances acquisition of cocaine self-administration in adult rats. This effect was specific to cocaine and not due to learning or performance differences.
View Article and Find Full Text PDFBackground: Recent studies of the relationship between the apolipoprotein E (APOE) gene and Alzheimer's disease in adults with Down's syndrome have revealed inconsistent results.
Aims: To assess the role of the APOE gene in the manifestation of Alzheimer's disease in adults with Down's syndrome.
Method: We studied the APOE genotypes of 24 adults with dementia and 33 non-demented adults with Down's syndrome over 35 years of age, and an additional group of 164 non-learning disabled adults.
We previously reported that neonatal isolation stress significantly changes measures of hippocampal long-term potentiation (LTP) in male and female juvenile rats, i.e., at 30 days of age.
View Article and Find Full Text PDFIn a series of sibpairs with late onset Alzheimer's disease, we have examined the segregation of the loci involved in the early onset, autosomal dominant form of the disorder by using flanking microsatellite repeat markers: thus we have used APP-PCR3 and D21S210 to examine the segregation of the amyloid-beta precursor protein (APP) gene, the markers DI 4S77 and D14S284 to examine the segregation of the presenilin 1 (PSI) gene and the markers D1S227, D1S249 and D1S419 to examine the segregation of presenilin 2 (PS2). We carried out our analyses on the whole dataset of 291 affected sibpairs, and on subsets comprising those sibpairs in which neither had an apolipoprotein E4 allele (65 affected sibpairs) and those in which both had an apolipoprotein E4 allele (165 affected sibpairs). We used the programs SPLINK to generate allele frequencies and MAPMAKER/SIBS to analyze our results.
View Article and Find Full Text PDFSonographic analysis of isolation-induced calls of 10- to 17-day-old Sprague-Dawley rat pups showed that average acoustic parameters of calls changed with pups' age. Average call duration increased with age from 80 ms to over 140 ms in 15-day-old pups. The peak frequency increased from approximately 50 kHz to an average of 64 kHz in 17-day-old pups, and the average bandwidth increased from 34 to 45 kHz in 17-day-old pups.
View Article and Find Full Text PDFRecent reports have suggested that variability in the alpha2-macroglobulin gene is a genetic risk factor for Alzheimer's disease. Here we have both tested a common polymorphism in the gene (I1000V) for association with the disease in a four-site case control study design, and tested the locus for linkage in a large series of sibpairs afflicted with late onset disease. Our results fail to show an association between this polymorphism and disease.
View Article and Find Full Text PDFAge of onset (AO) of Huntington disease (HD) is known to be correlated with the length of an expanded CAG repeat in the HD gene. Apolipoprotein E (APOE) genotype, in turn, is known to influence AO in Alzheimer disease, rendering the APOE gene a likely candidate to affect AO in other neurological diseases too. We therefore determined APOE genotype and normal CAG repeat length in the HD gene for 138 HD patients who were previously analysed with respect to CAG repeat length.
View Article and Find Full Text PDFWe have genotyped 292 affected sibling pairs (ASPs) with Alzheimer's disease (AD) according to NINCDS-ADRDA diagnostic criteria and with onset ages of >/=65 years using 237 microsatellite markers separated by an average distance of 16.3 cM. Data were analysed by SPLINK and MAPMAKER/SIBS on the whole sample of 292 ASPs and subsets of 162 ASPs where both members possessed an apolipoprotein E (APOE)straightepsilon4 allele and 63 pairs where neither possessed anstraightepsilon4 allele.
View Article and Find Full Text PDFIsolation of the rat pup from the nest and dam for one hour per day from PN 2-9 is a useful paradigm for producing stress in the neonate. These previously isolated rats respond to an amphetamine challenge with alterations in activity at the juvenile stage or as adults. Furthermore, when dopamine release is measured in the nucleus accumbens, juveniles release 3 times more dopamine after amphetamine than do controls.
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