Endosomal abnormalities related to amyloid precursor protein in cholesterol treated cerebral cortex neuronal cells derived from trisomy 16 mice,an animal model of Down syndrome

The CNh and CTb cell lines are derived from the cerebral cortex of normal and trisomy 16 mice, an animal model of human trisomy 21, Down syndrome (DS), and represent in vitro models to study cellular events associated with the human condition. Amyloid precursor protein (APP) plays an important role in the development of neuropathology associated with DS and cholesterol in the amyloidogenic processing of APP. There is also increasing evidence of alterations in the recycling pathway of the early endosome compartment in nervous tissue from DS. In the present study, we report endosomal abnormalities related to amyloid precursor protein in cholesterol-treated CTb cells. Colocalization studies revealed the presence of APP-derived products in early endosomal compartments in both cell lines. Using internalization and immunoprecipitation techniques, differential effects were observed between the normal and trisomic cell lines when treated with cholesterol. Internalization experiments showed that the CTb cell line accumulates internalized APP in intracellular compartments for longer periods of time when compared to the CNh cell line. Immunoprecipitation revealed a differential interaction between the trafficking-related protein Rab4 and APP in the neuronal cell lines CNh and CTb. The present study suggests a putative mechanism by which overexpressed APP accumulates in intracellular compartments related to the endosomal trafficking pathway in individuals with DS, and highlights the usefulness of the CTb cell line as a model to study altered APP metabolism related to this genetic condition.     

Object recognition memory is conserved in Ts1Cje,a mouse model of Down syndrome

Ts1Cje and Ts65Dn are genetic mouse models of Down syndrome (DS). Like individuals with DS, these mice exhibit various hallmarks of hippocampal pathology, and deficits in hippocampal-based, declarative learning and memory tasks. Both spatial navigation and novel object recognition, two prototypical domains of declarative memory function, have been strongly characterized in the Ts65Dn DS model. Indeed, Ts65Dn mice show navigation problems in the Morris water maze, impaired alternation in a T-maze, and deficient working and reference memory in the radial arm maze task. They, likewise, show an inability to detect object novelty over time. In contrast to the Ts65Dn model, hippocampal-dependent cognition has been less well characterized in Ts1Cje. Although Ts1Cje mice have been found to exhibit spatial difficulties in the Morris water maze and reduced spontaneous alternation, their ability to process object-based information has never been examined. Here, we report that Ts1Cje mice perform normally in short-term and long-term novel object recognition tasks. The ability of Ts1Cje mice to detect object novelty, unlike Ts65Dn, may point to differences in the extent of hippocampal pathology in the two DS mouse models.     

Down syndrome and dementia: a randomized, controlled trial of antioxidant supplementation

Individuals with Down syndrome over age 40 years are at risk for developing dementia of the Alzheimer type and have evidence for chronic oxidative stress. There is a paucity of treatment trials for dementia in Down syndrome in comparison to Alzheimer disease in the general (non-Down syndrome) population. This 2-year randomized, double-blind, placebo-controlled trial assessed whether daily oral antioxidant supplementation (900 IU of alpha-tocopherol, 200 mg of ascorbic acid and 600 mg of alpha-lipoic acid) was effective, safe and tolerable for 53 individuals with Down syndrome and dementia. The outcome measures comprised a battery of neuropsychological assessments administered at baseline and every 6 months. Compared to the placebo group, those individuals receiving the antioxidant supplement showed neither an improvement in cognitive functioning nor a stabilization of cognitive decline. Mean plasma levels of alpha-tocopherol increased ~2-fold in the treatment group and were consistently higher than the placebo group over the treatment period. Pill counts indicated good compliance with the regimen. No serious adverse events attributed to the treatment were noted. We conclude that antioxidant supplementation is safe, though ineffective as a treatment for dementia in individuals with Down syndrome and Alzheimer type dementia. Our findings are similar to studies of antioxidant supplementation in Alzheimer disease in the general population. The feasibility of carrying out a clinical trial for dementia in Down syndrome is demonstrated.     

Personal social networks of people with Down syndrome

Studies in the neurotypical population have demonstrated that personal social networks can mitigate cognitive decline and the development of Alzheimer disease. To assess whether these benefits can also be extended to people with Down syndrome (DS), we studied whether and how personal networks can be measured in this population. We adapted a personal networks instrument previously created, validated, and implemented for the neurotypical population. We created two versions of the survey: one for participants with DS, ages 25 and older, and another for their study partners, who spent a minimum of 10 h/wk in a caregiver role. Participants with DS gave concordant data to those of study partners. Their personal networks included a median network size of 7.50, density 0.80, constraint 46.00, and effective size 3.07. Personal networks were composed of 50% kin, 80% who live within 15 miles, and 80% who eat a healthy diet. In this proof-of-principle study, we demonstrated that the personal networks of people with DS can be quantitatively analyzed, with no statistical difference between self-report and parent-proxy report. Future research efforts can now evaluate interventions to enhance personal networks for preventing Alzheimer disease in this population.     

Nicotine modifies in vivo and in vitro rat hippocampal amyloid precursor protein processing in young but not old rats

Abnormally hyperphosphorylated microtubule-associated protein tau is the main component of the neurofibrillary tangles (NFT), a hallmark pathological feature of Alzheimer's disease (AD). A lot of studies suggested that there is highly neurobiological correlation between olfactory dysfunction and AD-like pathology, but the effect of the odor stimulation on tau phosphorylation remains unknown. Here, we examined the effect of short-term and long-term enriched odor exposure on the alterations of tau phosphorylation at multiple sites in the rat brains. We found that short-term odor enrichment did not affect the phosphorylation of tau, while long-term odor enrichment dramatically reduce the phosphorylation level of tau at Ser198/199/202, Thr231, Ser396, and Ser404 sites both in the hippocampus and cortex. These data suggest that long-term odor exposure prevent tau phosphorylation and may be a new therapeutic strategy of AD.     

Neutrophil oxidative metabolism in Down syndrome patients with congenital heart defects

Down syndrome (DS) occurs when an individual has three, rather than two, copies of the 21st chromosome. Cytosolic superoxide dismutase (SOD‐1) is encoded by a gene on chromosome 21 and thus, SOD‐1 activity is elevated in patients with DS. Forty percent of all cases with DS are associated with congenital heart defects (CHD). Although the contribution of SOD1 to disease phenotype is unknown, it is considered to be a “molecular marker” of the disease. It was hypothesized herein that the presence of CHD may alter the expression of SOD1 and oxidative metabolism in patients with DS. This hypothesis was tested via four experimental groups as follows: patients with DS without CHD, DS patients with CHD, CHD patients without DS and controls. Expression and activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), myeloperoxidase (MPO), and catalase (CAT) were determined in neutrophils from all experimental groups. Intracellular hydrogen peroxide concentration and superoxide release were also evaluated in neutrophils. A significant increase was observed in SOD and GPx amount and activity in patients with DS with and without CHD. No significant difference was found in the amount and activity of MPO and CAT among the different experimental groups. Intracellular hydrogen peroxide concentration was similar in all groups, whereas a prominent decrease was seen in superoxide release in cases with DS. Patients with DS with and without CHD showed no significant differences in any of the measured parameters. The data suggest that CHD observed in patients with DS does not result from altered redox metabolism associated with the disease. Environ. Mol. Mutagen., 2010. © 2009 Wiley‐Liss, Inc.     

Mutational screening of APP gene in patients with early-onset Alzheimer disease utilizing mismatched PCR-RFLP

To elucidate the frequency of mutations of the β/A4 amyloid protein precursor (APP) gene in early-onset Alzheimer disease, we designed a mismatched PCR-RFLP that can identify all kinds of missense mutations at codon 717 in addition to the seven kinds of known mutations at exon 17. When we screened mutations at exon 17 utilizing this method and the double missense mutations at exon 16 of the APP gene by PCR-RFLP, no cases revealed mutations of the APP gene among 13 familial and 54 sporadic cases, except one family (OS-1) that had previously been reported and used as a positive control of APP717(Val → Ile). Our results support the hypothesis that mutations in the APP gene are not major causes in early-onset Alzheimer disease.     

Acquired glomerular lesions in patients with Down syndrome

The long-term survival of persons with Down syndrome has dramatically increased over the past 50 years. There are no studies addressing the spectrum of glomerular lesions in these patients. We reviewed the clinical-pathologic characteristics of 17 patients with Down syndrome who underwent renal biopsy. The cohort consisted of 12 whites and 5 African Americans with mean age of 29 years (range, 6-45 years). History of hypothyroidism was present in 8 patients. Renal presentations included renal insufficiency (15 patients, mean serum creatinine 3.4 mg/dL), proteinuria (all patients, including 3 with nephrotic syndrome, mean 24-hour urine protein 4.2 g), and hematuria (14 patients, including 4 with gross hematuria). The glomerular diseases found on biopsy were IgA nephropathy (n = 5 patients), focal segmental glomerulosclerosis (n = 4), membranoproliferative glomerulonephritis (n = 2), acute postinfectious glomerulonephritis (n = 2), pauci-immune crescentic glomerulonephritis (n = 2), membranous glomerulonephritis (n = 1), and lupus nephritis (n = 1). Follow-up (mean, 47 months; range, 2-141 months) was available on 16 patients (94%). Two patients (1 with membranous glomerulonephritis and 1 with acute postinfectious glomerulonephritis) had complete remission; 8 patients (4 with IgA nephropathy, 2 with focal segmental glomerulosclerosis, 1 with lupus nephritis, and 1 with acute postinfectious glomerulonephritis) had chronic kidney disease; and 6 patients (2 with pauci-immune crescentic glomerulonephritis, 2 with membranoproliferative glomerulonephritis, 1 with IgA nephropathy, and 1 with focal segmental glomerulosclerosis) progressed to end-stage renal disease, 4 of whom died. In summary, a wide spectrum of glomerular diseases can be seen in patients with Down syndrome, with IgA nephropathy and focal segmental glomerulosclerosis being the most common. Renal biopsy is necessary to determine the type of glomerular lesion and appropriate treatment.     

Increased low-level chromosome 21 mosaicism in older individuals with Down syndrome

During a study of the familial aggregation of Down syndrome (DS) and Alzheimer disease (AD), we observed an increase in mosaicism for disomy 21 in older individuals with DS. In a total of 213 DS subjects who were studied cytogenetically, only 1 of 121 (0.8%) under age 45 exhibited mosaicism, while 14 of 92 (15.2%) who were age 45 or older had mosaicism. Mosaicism in this report connotes “low-level” mosaicism, where all 15 individuals exhibited a modal chromosome number of 47 (i.e., trisomy 21), and at least two cells lacked one of the three chromosomes 21. The occurrence of aneuploidy for chromosomes 15, 17, and X increased with age, and an inverse correlation between chromosome loss and size was also observed. Because older individuals had not been karyotyped at birth, it was not possible to determine whether our observations were due to either increased survival of mosaic individuals or accumulation of disomy 21 cells via increased chromosome loss with aging of the trisomy 21 individual. Using a modeling approach involving life table methods, we obtained results that suggested acquired mosaicism as the predominant mechanism to explain our findings. These results support the hypothesis that as individuals with DS age, there is an increased loss of chromosome 21. Am. J. Med. Genet. 68:147–151, 1997 © 1997 Wiley-Liss, Inc.     

Neopterin and the risk of dementia in persons with Down syndrome

Persons with Down syndrome show an altered immune response and an increased susceptibility to Alzheimer's disease. In a prospective study, we examined whether the plasma neopterin level, a marker for cell-mediated immune activation and inflammation, is associated with an increased risk of dementia in persons with Down syndrome. Plasma concentrations of neopterin were determined in a population-based study of 394 persons with Down syndrome, who were screened annually for dementia. We used Cox proportional hazards model to determine risk of dementia. Demented persons with Down syndrome have a significantly (p = 0.05) higher plasma neopterin concentration than the non-demented. In the non-demented without autoimmune disorders, in those with a plasma level of neopterin above median, the risk to develop dementia increased to 1.83 (95% confidence interval: 1.04–3.20). High plasma neopterin level is an independent determinant of the risk of dementia in persons with Down syndrome.     

Cytogenetic,epidemiological and clinical profile of children with Down syndrome in Karnataka

Introduction

Down syndrome is one of the best recognized and the most common chromosomal aneuploidy with high life expectancy than other chromosomal aneuploidies. The clinical features are quite distinguishing and easily identifiable, but a karyotype analysis is always better to confirm the diagnosis. It is also needed for calculating the risk of recurrence and for genetic counseling. This study was done to analyze the clinical features, cytogenetic and epidemiological profile of Down syndrome children in Tumkur and Bangalore region of Karnataka.

Pedigrees of 30 families with Alzheimer disease: Associations with defective organization of microfilaments and microtubules

A study of 30 families located through a proband with Alzheimer disease discovered highly significant excesses of Down syndrome and immunocytic cancer. A genetic disorder of immune function mediated by microtubules and microfilaments is suggested by the data. The pedigrees of the Alzheimer families are presented.Abbreviations and explanation of terms in pedigrees CVA cerebral vascular accident - CVD cerebral vascular disease; diabetes, all took insulin or were most likely insulin dependent; flu, all refere to 1918–1919 pandemic - HCVRD hypertensive cardiovascular-renal disease - IHD ischemic heart disease; quotes, all from death certificates - RVD rheumatic valvular disease     

Survival of children with Down syndrome in South America

The first step of all healthcare actions aimed at promoting an appropriate quality of life for infants affected by Down syndrome (DS) is to ensure their survival. This investigation was aimed at estimating the infant mortality rate of infants affected with DS in urban populations of South America. Thirty-three hospitals included in the Latin American Collaborative Study of Congenital Malformations (ECLAMC) distributed in 23 cities of 5 South American countries followed 360 liveborn DS cases born during the 1988–1992 period. Families were recontacted after the infant should have reached the age of one year. The collected data included information about health status; i.e., frequency and dates of diagnosed illnesses and hospital admissions, and, in case of death, information on date, place and cause of death, and illness immediately before death. Information about the interviews included place, date, and name of the interviewer. A closed questionnaire was employed by the interviewers, mostly physicians, nurses, and social workers. Life table analysis up to the age of one year was performed by the actuarial survival method. The overall mean survival at age one year was 0.736 (SE = 0.023). Thirty-three (9.2%) of the 360 cases died neonatally, and 62 (17.2%) within the remaining 2-to-12-month interval. The probability of survival at one year of age did not differ between public (209 cases; mean 0.718; SE = 0.031) and private (151 cases; mean: 0.762; SE = 0.035) (χ²:0.87; df:1; P >0.05) health systems. The 150 DS cases with a congenital heart defect (CHD) had a significantly lower P robability of survival at the age of one year (mean: 0.660; SE: 0.039) than did the 210 cases without CHD (mean: 0.790; SE: 0.028) (χ²:6.67; df:1; P <0.01). The death rate in the first year of life for DS cases without a detected cardiac defect (21%) is significantly higher than that reported in developed countries; namely, 16% from Italy, 11% from Canada, 10% from England, and 7% from Denmark. Am. J. Med. Genet. 79:108–111, 1998. © 1998 Wiley-Liss, Inc.     

Elevated expression of beta-site amyloid precursor protein cleaving enzyme 2 in brains of patients with Down syndrome

The gene encoding the beta-site amyloid precursor protein cleaving enzyme 2 (BACE2) has been determined to be located on the long arm of chromosome 21 at 21q22.3. BACE2 cleaves the amyloid precursor protein at the beta-secretase site and is thought to contribute to amyloid beta protein production. In the present study, changes in the expression of BACE2 were investigated immunohistochemically in the frontal cortex of patients with Down syndrome (DS). The immunoreactivity for BACE2 was detected in neurofibrillary tangle-bearing neurons from the elderly DS brains with Alzheimer-type neuropathology, but were not detected in those of DS brains without Alzheimer-type neuropathology or of control brains of any age. This suggests the possibility that the elevated expression of BACE2 is involved in the Alzheimer-type neuropathology of DS.     

Cholesterol level, statin use and Alzheimer's disease in adults with Down syndrome

Adults with Down syndrome (DS) are at significantly higher risk of Alzheimer's disease (AD) than the general population, but there is considerable variability in age at onset. This study tested the hypothesis that total cholesterol (TC) levels are related to vulnerability, and that the use of statins may decrease risk. The relation of TC level and statin use to risk of AD was investigated in 123 Caucasian adults with DS. Evaluations included serial assessments of cognitive, adaptive and maladaptive behavior, medical records, and neurological examinations. Mean length of follow-up was 5.5 years [1.2-7.1] for the entire sample, 5.1 years [1.2-7.1] for subjects who developed dementia, and 5.6 years [1.5-7.1] for those who did not develop dementia. Controlling for covariates, participants with TC>or=200mg/dL were more than two times as likely to develop AD than subjects with lower TC [hazard rate (HR)=2.59, p=.029, 95% CI: 1.1, 6.1]. In contrast, participants with higher TC levels who used statins during the study, had less than half the risk of developing AD than participants with higher TC levels who did not use statins (HR=.402, p=.095, 95% CI: .138, 1.173). If the protective effects of statins can be further validated, these findings suggest that their use may delay or prevent AD onset in vulnerable populations.     

SORL1 is genetically associated with increased risk for late-onset Alzheimer disease in the Belgian population

SORL1 has recently been identified as a major genetic contributor to increased risk for late-onset Alzheimer disease (AD). Here we aimed at replicating this finding in a large, well-characterized group of 550 Belgian late-onset AD patients and 637 healthy control individuals using a gene-wide genotyping approach across the SORL1 locus. We observed significant associations, both for individual SNPs (SNPs 6, 8, 9, 10 and 27; p-values ranging from 0.001 to 0.040) and 3-SNP haplotypes (SNPs 5-6-7 and SNPs 25-26-27; p-values ranging from 0.008 to 0.035). Moreover, the associations at SNP 8, 9 and 10 represented a direct replication of the initial association data. Two signals in distinct regions of the gene were shown to be mutually independent, supporting allelic heterogeneity at the SORL1 locus in the Belgian population. Our findings confirm that genetic variants in SORL1 may be important risk factors for late-onset AD.     

Association of variants within APOE, SORL1, RUNX1, BACE1 and ALDH18A1 with dementia in Alzheimer's disease in subjects with Down syndrome

Background: Down syndrome (DS) is caused by either complete or partial triplication of chromosome 21, affecting approximately 1/1000 live births, and it is widely accepted that individuals with DS are more likely to develop dementia of Alzheimer's disease (DAD) compared with the general population. Many studies have investigated genetic susceptibility to AD in the general population, resulting in a number of potential candidate genes that may influence the development of DAD. The majority of these variants, however, have not been investigated in subjects with DS. Aim: The aim of this study was to determine whether genetic variants previously associated with AD in the general population, were also associated with DAD in individuals with DS. Methods: Genotyping of 43 SNPs within 28 genes was undertaken in 187 individuals with Down syndrome with and without dementia of Alzheimer's disease, using the SNPlex platform. Results: Significant associations of SNPs in five genes with DAD in DS were found, namely APOE, SORL1, BACE1, RUNX1 and ALDH18A1. As expected, the most strongly associated SNP was the APOE ?4 rs429358 variant (HR = 2.47 [1.58, 3.87], p = 7.52 × 10⁻⁵), although variants within the more recently implicated SORL1 and RUNX1 genes were also strongly associated with DAD in DS (HR = 0.54 [0.37, 0.80], p = 0.002 and HR = 1.61 [1.15, 2.26], p = 0.006 respectively). Conclusions: Our study demonstrates that a number of variants previously associated with AD in the general population are also associated with DAD in DS. To enable us to determine whether these variants, as well as other more recently revealed AD susceptibility variants, truly contribute to the development of DAD in DS, further multi-centre collaborative studies comprising large number of individuals with DS are needed.