A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome.
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ABSTRACT:
SUBMITTER: Wiseman FK
PROVIDER: S-EPMC4678594 | biostudies-literature | 2015 Sep
REPOSITORIES: biostudies-literature
Publications
A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome.
Wiseman Frances K FK Al-Janabi Tamara T Hardy John J Karmiloff-Smith Annette A Nizetic Dean D Tybulewicz Victor L J VL Fisher Elizabeth M C EM Strydom André A
Nature reviews. Neuroscience 20150805 9
Down syndrome, which arises in individuals carrying an extra copy of chromosome 21, is associated with a greatly increased risk of early-onset Alzheimer disease. It is thought that this risk is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP)--an Alzheimer disease risk factor--although the possession of extra copies of other chromosome 21 genes may also play a part. Further study of the mechanisms underlying the development of Alzheimer disease in pe ...[more]
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Project description:ObjectiveAdults with Down syndrome (DS) develop Alzheimer disease (AD) pathology by their 5th decade. Compared with the general population, traditional vascular risks in adults with DS are rare, allowing examination of cerebrovascular disease in this population and insight into its role in AD without the confound of vascular risk factors. We examined in vivo magnetic resonance imaging (MRI)-based biomarkers of cerebrovascular pathology in adults with DS, and determined their cross-sectional relationship with age, beta-amyloid pathology, and mild cognitive impairment or clinical AD diagnostic status.MethodsParticipants from the Biomarkers of Alzheimer's Disease in Down Syndrome study (n = 138, 50 ± 7 years, 39% women) with MRI data and a subset (n = 90) with amyloid positron emission tomography (PET) were included. We derived MRI-based biomarkers of cerebrovascular pathology, including white matter hyperintensities (WMH), infarcts, cerebral microbleeds, and enlarged perivascular spaces (PVS), as well as PET-based biomarkers of amyloid burden. Participants were characterized as cognitively stable (CS), mild cognitive impairment-DS (MCI-DS), possible AD dementia, or definite AD dementia based on in-depth assessments of cognition, function, and health status.ResultsThere were detectable WMH, enlarged PVS, infarcts, and microbleeds as early as the 5th decade of life. There was a monotonic increase in WMH volume, enlarged PVS, and presence of infarcts across diagnostic groups (CS < MCI-DS < possible AD dementia < definite AD dementia). Higher amyloid burden was associated with a higher likelihood of an infarct.InterpretationThe findings highlight the prevalence of cerebrovascular disease in adults with DS and add to a growing body of evidence that implicates cerebrovascular disease as a core feature of AD and not simply a comorbidity. ANN NEUROL 2020;88:1165-1177.
| S-EPMC7729262 | biostudies-literature
Project description:ImportancePeople with Down syndrome have a high risk of developing Alzheimer disease dementia. However, penetrance and age at onset are considered variable, and the association of this disease with life expectancy remains unclear because of underreporting in death certificates.ObjectiveTo assess whether the variability in symptom onset of Alzheimer disease in Down syndrome is similar to autosomal dominant Alzheimer disease and to assess its association with mortality.Design, setting, and participantsThis study combines a meta-analysis with the assessment of mortality data from US death certificates (n = 77 347 case records with a International Classification of Diseases code for Down syndrome between 1968 to 2019; 37 900 [49%] female) and from a longitudinal cohort study (n = 889 individuals; 46% female; 3.2 [2.1] years of follow-up) from the Down Alzheimer Barcelona Neuroimaging Initiative (DABNI).Main outcomes and measuresA meta-analysis was conducted to investigate the age at onset, age at death, and duration of Alzheimer disease dementia in Down syndrome. PubMed/Medline, Embase, Web of Science, and CINAHL were searched for research reports, and OpenGray was used for gray literature. Studies with data about the age at onset or diagnosis, age at death, and disease duration were included. Pooled estimates with corresponding 95% CIs were calculated using random-effects meta-analysis. The variability in disease onset was compared with that of autosomal dominant Alzheimer disease. Based on these estimates, a hypothetical distribution of age at death was constructed, assuming fully penetrant Alzheimer disease. These results were compared with real-world mortality data.ResultsIn this meta-analysis, the estimate of age at onset was 53.8 years (95% CI, 53.1-54.5 years; n = 2695); the estimate of age at death, 58.4 years (95% CI, 57.2-59.7 years; n = 324); and the estimate of disease duration, 4.6 years (95% CI, 3.7-5.5 years; n = 226). Coefficients of variation and 95% prediction intervals of age at onset were comparable with those reported in autosomal dominant Alzheimer disease. US mortality data revealed an increase in life expectancy in Down syndrome (median [IQR], 1 [0.3-16] years in 1968 to 57 [49-61] years in 2019), but with clear ceiling effects in the highest percentiles of age at death in the last decades (90th percentile: 1990, age 63 years; 2019, age 65 years). The mortality data matched the limits projected by a distribution assuming fully penetrant Alzheimer disease in up to 80% of deaths (corresponding to the highest percentiles). This contrasts with dementia mentioned in 30% of death certificates but is in agreement with the mortality data in DABNI (78.9%). Important racial disparities persisted in 2019, being more pronounced in the lower percentiles (10th percentile: Black individuals, 1 year; White individuals, 30 years) than in the higher percentiles (90th percentile: Black individuals, 64 years; White individuals, 66 years).Conclusions and relevanceThese findings suggest that the mortality data and the consistent age at onset were compatible with fully penetrant Alzheimer disease. Lifespan in persons with Down syndrome will not increase until disease-modifying treatments for Alzheimer disease are available.
| S-EPMC9127560 | biostudies-literature
Project description:Background Death certificates are crucial for understanding population health trends including the burden of disease mortality. Accurate reporting of causes of death on these records is necessary in order to implement adequate public health policies and fund disease research. While there is evidence that Alzheimer disease and unspecified dementia are prevalent among people with Down syndrome, a 2014 Centers for Disease Control and Prevention (CDC) rule change instructing that Down syndrome should be reported as the underlying cause of death in instances when death occurred from Alzheimer disease or unspecified dementia threatens the accuracy and the utility of death certificates for this population. Methods This study used 15 years (2005–2019) of US death certificate data for adults with and without Down syndrome. We compare the mortality burden due to Alzheimer disease and unspecified dementia prior to and after amending death certificates that report Down syndrome as the underlying cause of death. Results When analyzing death certificates without addressing the reporting of Down syndrome as the underlying cause of death, rates of death due to Alzheimer disease and dementia ranked as the third leading cause of death for both adults with and without Down syndrome. After amending death certificates that reported Down syndrome as the underlying cause of death, Alzheimer disease and dementia were the leading cause of death among those with Down syndrome, occurring 2.7 times more in adults with compared to without Down syndrome. Conclusion The findings of this study highlight the importance of accurate mortality data for studying and addressing population health trends. The current practice of reporting Down syndrome as the underlying cause of death rather than the disease responsible for death needs to be reconsidered and modified. If not, people with Down syndrome may be further marginalized within dementia related support and research.
| S-EPMC9925077 | biostudies-literature
Project description:Background: People with Down Syndrome (DS) are born with an extra copy of Chromosome (Chr) 21 and many of these individuals develop Alzheimer's Disease (AD) when they age. This is due at least in part to the extra copy of the APP gene located on Chr 21. By 40 years, most people with DS have amyloid plaques which disrupt brain cell function and increase their risk for AD. About half of the people with DS develop AD and the associated dementia around 50 to 60 years of age, which is about the age at which the hereditary form of AD, early onset AD, manifests. In the absence of Chr 21 trisomy, duplication of APP alone is a cause of early onset Alzheimer's disease, making it likely that having three copies of APP is important in the development of AD and in DS. Methods: We investigate the relationship between AD and DS through integrative analysis of genesets derived from a MeSH query of AD and DS associated beta amyloid peptides, Chr 21, GWAS identified AD risk factor genes, and differentially expressed genes in individuals with DS. Results: Unique and shared aspects of each geneset were evaluated based on functional enrichment analysis, transcription factor profile and network interactions. Genes that may be important to both disorders in the context of direct association with APP processing, Tau post translational modification and network connectivity are ACSM1, APBA2, APLP1, BACE2, BCL2L, COL18A1, DYRK1A, IK, KLK6, METTL2B, MTOR, NFE2L2, NFKB1, PRSS1, QTRT1, RCAN1, RUNX1, SAP18 SOD1, SYNJ1, S100B. Conclusions: Our findings confirm that oxidative stress, apoptosis, inflammation and immune system processes likely contribute to the pathogenesis of AD and DS which is consistent with other published reports.
| S-EPMC7871416 | biostudies-literature
Project description:BackgroundImpaired axonal transport may contribute to the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD) and Down syndrome (DS). Axonal transport is a complex process in which specific motor proteins move cargoes to and from neuronal cell bodies and their processes. Inconsistent reports point to the changes in AD in the levels of the classical anterograde motor protein kinesin family member 5 (KIF5) and the primary neuronal KIF regulator kinesin light chain 1 (KLC1), raising the possibility that anterograde transport is compromised in AD.Methods and materialsTo address inconsistencies and determine if the shared pathologies in AD and elderly DS subjects with dementia (AD in DS; AD-DS) extend to the changes in KIF5 and KLC1, we measured the levels of all the three KIF5 family members and KLC1 in the AD and AD-DS frontal cortex and AD temporal cortex and cerebellum in samples taken with a short postmortem interval. To support future studies to explore the cell biological basis for any changes detected, we also examined the levels of these proteins in the brains of young and aged adult mice in the Dp (16)1Yey/+ (Dp16) mouse model of DS and J20 mouse model of AD.ResultsThere were no changes in comparison with controls in KIF5 family members in either the AD or AD-DS samples when normalized to either β-actin or glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Interestingly, however, samples from control brains as well as from AD and AD-DS demonstrated strong positive correlations between the levels of KIF5 family members, suggesting positive co-regulated expression. Importantly, while earlier reports pointed to a negative correlation between the levels of the amyloid precursor protein (APP) and KIF5A levels, we found the opposite to be true in AD-DS; this was especially striking given triplication of the APP gene, with increased APP protein levels. AD and control samples showed positive correlations between fl-hAPP and KIF5 members, but they were less consistent. In contrast to the findings for KIF5, the levels of KLC1 were downregulated in the frontal cortex of both AD and AD-DS brains; interestingly, this change was not seen in the AD temporal cortex or cerebellum. As postmortem interval has a negative effect on the levels of KLC1, but not KIF5 members, we analyzed a subset of samples with a very short postmortem interval (PMI) (≤ 6 h), a PMI that was not significantly correlated with the levels of KLC1 in either AD or AD-DS samples; we confirmed the presence of a statistically significant reduction of KLC1 in AD and AD-DS brains as compared with control brains. Studies comparing Dp16 to its euploid control recapitulated human studies in demonstrating no change in KIF5 levels and a positive correlation between the levels of KIF5 family members. J20 mice also showed normal KIF5 levels. However, unlike the AD and AD-DS frontal cortex, KLC1 levels were not reduced in the brains of Dp16 or J20 mice.ConclusionThese data point to significant reductions in KLC1 in AD and AD-DS. In so doing, they raise the possibility of compromised KLC1-mediated axonal transport in these conditions, a posit that can now be pursued in model systems in which KLC1 expression is reduced.
| S-EPMC7945332 | biostudies-literature
Project description:The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase involved in the regulation of protein synthesis and degradation, longevity and cytoskeletal formation. The mTOR pathway represents a key growth and survival pathway involved in several diseases such as cancer, obesity, cardiovascular disease and neurodegenerative diseases. Numerous studies linked the alterations of mTOR pathway to age-dependent cognitive decline, pathogenesis of Alzheimer disease (AD) and AD-like dementia in Down syndrome (DS). DS is the most frequent chromosomal abnormality that causes intellectual disability. The neuropathology of AD in DS is complex and involves impaired mitochondrial function, defects in neurogenesis, increased oxidative stress, altered proteostasis and autophagy networks as a result of triplication of chromosome 21(chr 21). The chr21 gene products are considered a principal neuropathogenic moiety in DS. Several genes involved respectively in the formation of senile plaques and neurofibrillary tangles (NFT), two main pathological hallmarks of AD, are mapped on chr21. Further, in subjects with DS the activation of mTOR signaling contributes to A? generation and the formation of NFT. This review discusses recent research highlighting the complex role of mTOR associated with the presence of two hallmarks of AD pathology, senile plaques (composed mostly of fibrillar Aß peptides), and NFT (composed mostly of hyperphosphorylated tau protein). Oxidative stress, associated with chr21-related A? and mitochondrial alterations, may significantly contribute to this linkage of mTOR to AD-like neuropathology in DS.
| S-EPMC5748251 | biostudies-other
Project description:Advances in gerontology have yielded crucial insights into the molecular and biochemical aspects of the ageing process. The sirtuin pathway, which is most notable for its association with the anti-ageing effects of calorie restriction, has received particular attention, and pharmacological or transgenic upregulation of the sirtuin pathway has shown promising results in laboratory models of ageing. Alzheimer's disease is a neurodegenerative disease that is imposing an increasing burden on society, and is the leading cause of senile dementia worldwide. The lack of therapies for Alzheimer's disease provides a strong incentive for the development of an effective treatment strategy and, interestingly, research has uncovered a mechanism of action of the sirtuin pathway that might have therapeutic potential for Alzheimer's disease.SIRT1, one of the seven mammalian proteins of the sirtuin family of NAD(+)-dependent deacetylases, has recently been shown to attenuate amyloidogenic processing of amyloid-? protein precursor (APP) in cell culture studies in vitro and in transgenic mouse models of Alzheimer's disease. Mechanistically, SIRT1 increases ?-secretase production and activity through activation of the ?-secretase gene ADAM10. Because ?-secretase is the enzyme responsible for the non-amyloidogenic cleavage of APP, upregulation of ?-secretase shifts APP processing to reduce the pathological accumulation of the presumptive toxic A? species that results from ?-secretase and ?-secretase activity. Interestingly, the spatial patterns of A? deposition in the brain might correlate with increased aerobic glycolysis in those regions. Because aerobic glycolysis depletes cellular levels of NAD(+) (through a decreased NAD(+)/NADH ratio), it is possible that a corresponding downregulation of the NAD(+)-dependent sirtuin pathway contributes to the amyloidogenic processing of APP. WHERE NEXT?: The specific inhibition of A? generation by SIRT1 coupled with the potential link between aerobic glycolysis, NAD(+) depletion, and amyloidogenesis through the sirtuin pathway has translational implications. On the one hand, the possible underlying role of the sirtuin pathway in Alzheimer's disease onset and development might increase our understanding of this devastating condition. On the other hand, therapeutic upregulation of SIRT1 might provide opportunities for the amelioration of Alzheimer's-disease-type neuropathology through inhibition of amyloidogenesis. Ultimately, further analysis into both aspects is necessary if any progress is to be made.
| S-EPMC3163839 | biostudies-other
Project description:Down syndrome (DS) is the most common non-lethal genetic condition that affects approximately 1 in 700 births in the United States of America. DS is characterized by complete or segmental chromosome 21 trisomy, which leads to variable intellectual disabilities, progressive memory loss, and accelerated neurodegeneration with age. During the last three decades, people with DS have experienced a doubling of life expectancy due to progress in treatment of medical comorbidities, which has allowed this population to reach the age when they develop early onset Alzheimer's disease (AD). Individuals with DS develop cognitive and pathological hallmarks of AD in their fourth or fifth decade, and are currently lacking successful prevention or treatment options for dementia. The profound memory deficits associated with DS-related AD (DS-AD) have been associated with degeneration of several neuronal populations, but mechanisms of neurodegeneration are largely unexplored. The most successful animal model for DS is the Ts65Dn mouse, but several new models have also been developed. In the current review, we discuss recent findings and potential treatment options for the management of memory loss and AD neuropathology in DS mouse models. We also review agerelated neuropathology, and recent findings from neuroimaging studies. The validation of appropriate DS mouse models that mimic neurodegeneration and memory loss in humans with DS can be valuable in the study of novel preventative and treatment interventions, and may be helpful in pinpointing gene-gene interactions as well as specific gene segments involved in neurodegeneration.
| S-EPMC5034871 | biostudies-literature
Project description:Severe periodontitis is prevalent in Down syndrome (DS). This study aimed to identify genetic variations associated with periodontitis in individuals with DS. The study group was distributed into DS patients with periodontitis (n = 50) and DS patients with healthy periodontium (n = 36). All samples were genotyped with the "Axiom Spanish Biobank" array, which contains 757,836 markers. An association analysis at the individual marker level using logistic regression, as well as at the gene level applying the sequence kernel association test (SKAT) was performed. The most significant genes were included in a pathway analysis using the free DAVID software. C12orf74 (rs4315121, p = 9.85 × 10-5, OR = 8.84), LOC101930064 (rs4814890, p = 9.61 × 10-5, OR = 0.13), KBTBD12 (rs1549874, p = 8.27 × 10-5, OR = 0.08), PIWIL1 (rs11060842, p = 7.82 × 10-5, OR = 9.05) and C16orf82 (rs62030877, p = 8.92 × 10-5, OR = 0.14) showed a higher probability in the individual analysis. The analysis at the gene level highlighted PIWIL, MIR9-2, LHCGR, TPR and BCR. At the signaling pathway level, PI3K-Akt, long-term depression and FoxO achieved nominal significance (p = 1.3 × 10-2, p = 5.1 × 10-3, p = 1.2 × 10-2, respectively). In summary, various metabolic pathways are involved in the pathogenesis of periodontitis in DS, including PI3K-Akt, which regulates cell proliferation and inflammatory response.
| S-EPMC8230717 | biostudies-literature
Project description:Human sodium-independent glucose cotransporter 1 (hGLUT1) has been studied for its tetramerization and multimerization at the cell surface. Homozygous or compound heterozygous mutations in hGLUT1 elicit GLUT1-deficiency syndrome (GLUT1-DS), a metabolic disorder, which results in impaired glucose transport into the brain. The reduced cell surface expression or loss of function have been shown for some GLUT1 mutants. However, the mechanism by which deleterious mutations affect protein structure, conformational stability and GLUT1 oligomerization is not known and require investigation. In this review, we combined previous knowledge of GLUT1 mutations with hGLUT1 crystal structure to analyze native interactions and several natural single-point mutations. The modeling of native hGLUT1 structure confirmed the roles of native residues in forming a range of side-chain interactions. Interestingly, the modeled mutants pointed to the formation of a variety of non-native novel interactions, altering interaction networks and potentially eliciting protein misfolding. Self-aggregation of the last part of hGLUT1 was predicted using protein aggregation prediction tool. Furthermore, an increase in aggregation potential in the aggregation-prone regions was estimated for several mutants suggesting increased aggregation of misfolded protein. Protein stability change analysis predicted that GLUT1 mutant proteins are unstable. Combining GLUT1 oligomerization behavior with our modeling, aggregation prediction, and protein stability analyses, this work provides state-of-the-art view of GLUT1 genetic mutations that could destabilize native interactions, generate novel interactions, trigger protein misfolding, and enhance protein aggregation in a disease state.
| S-EPMC7150661 | biostudies-literature