BACKGROUND:Amyloid-β (Aβ) is a principal cleavage product of amyloid-β protein precursor (AβPP) and is widely recognized as a key pathogenic player in Alzheimer's disease (AD). Yet, there is increasing evidence of a neurotoxic role for the AβPP intracellular domain (AICD) which has been proposed to occur through its nuclear function. Intriguingly, there is a γ-secretase resident at the mitochondria which could produce AICD locally.OBJECTIVE:We examined the potential of AICD to induce neuronal apoptosis when targeted specifically to the mitochondria and compared its mechanism of neurotoxicity to that of Aβ.METHODS:We utilized transient transfection of HT22 neuronal cells with bicistronic plasmids coding for DsRed and either empty vector (Ires), Aβ, AICD59, or mitochondrial-targeted AICD (mitoAICD) in combination with various inhibitors of pathways involved in apoptosis.RESULTS:AICD induced significant neuronal apoptosis only when targeted to the mitochondria. Apoptosis required functional mitochondria as neither Aβ nor mitoAICD induced significant toxicity in cells devoid of mitochondrial DNA. Both glutathione and a Bax inhibitor protected HT22 cells from either peptide. However, inhibition of the mitochondrial permeability transition pore only protected from Aβ, while pan-caspase inhibitors uniquely rescued cells from mitoAICD.CONCLUSION:Our results show that AICD displays a novel neurotoxic function when targeted to mitochondria. Moreover, mitoAICD induces apoptosis via a mechanism that is distinct from that of Aβ. These findings suggest that AICD produced locally at mitochondria via organelle-specific γ-secretase could act in a synergistic manner with Aβ to cause mitochondrial dysfunction and neuronal death in AD.

In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR). 5-PRA is extremely unstable under physiological conditions and is unlikely to accumulate in the absence of GART activity. Recently, a HeLa cell line null mutant for GART was constructed via CRISPR-Cas9 mutagenesis. This cell line, crGART, is an important cellular model of DNPS inactivation that does not accumulate DNPS pathway intermediates. In the current study, we characterized the crGART versus HeLa transcriptomes in purine-supplemented and purine-depleted growth conditions. We observed multiple transcriptome changes and discuss pathways and ontologies particularly relevant to Alzheimer disease and Down syndrome. We selected the Cluster of Differentiation (CD36) gene for initial analysis based on its elevated expression in crGART versus HeLa as well as its high basal expression, high log2 value, and minimal P-value.

We analyze the metabolomes of humans, chimpanzees, and macaques in muscle, kidney and three different regions of the brain. Although several compounds in amino acid metabolism occur at either higher or lower concentrations in humans than in the other primates, metabolites downstream of adenylosuccinate lyase, which catalyzes two reactions in purine synthesis, occur at lower concentrations in humans. This enzyme carries an amino acid substitution that is present in all humans today but absent in Neandertals. By introducing the modern human substitution into the genomes of mice, as well as the ancestral, Neandertal-like substitution into the genomes of human cells, we show that this amino acid substitution contributes to much or all of the reduction of de novo synthesis of purines in humans.

BACKGROUND: Recent advances in medical care have increased life expectancy and improved the quality of life for people with Down syndrome (DS). These advances are the result of both pre-clinical and clinical research but much about DS is still poorly understood. In 2020, the NIH announced their plan to update their DS research plan and requested input from the scientific and advocacy community. OBJECTIVE: The National Down Syndrome Society (NDSS) and the LuMind IDSC Foundation worked together with scientific and medical experts to develop recommendations for the NIH research plan. METHODS: NDSS and LuMind IDSC assembled over 50 experts across multiple disciplines and organized them in eleven working groups focused on specific issues for people with DS. RESULTS: This review article summarizes the research gaps and recommendations that have the potential to improve the health and quality of life for people with DS within the next decade. CONCLUSIONS: This review highlights many of the scientific gaps that exist in DS research. Based on these gaps, a multidisciplinary group of DS experts has made recommendations to advance DS research. This paper may also aid policymakers and the DS community to build a comprehensive national DS research strategy.

Down syndrome (DS) is a form of accelerated aging, and people with DS are highly prone to aging-related conditions that include vascular and neurological disorders. Due to the overexpression of several genes on Chromosome 21, for example genes encoding amyloid precursor protein (APP), superoxide dismutase (SOD), and some of the interferon receptors, those with DS exhibit significant accumulation of amyloid, phospho-tau, oxidative stress, neuronal loss, and neuroinflammation in the brain as they age. In this review, we will summarize the major strides in this research field that have been made in the last few decades, as well as discuss where we are now, and which research areas are considered essential for the field in the future. We examine the scientific history of DS bridging these milestones in research to current efforts in the field. We extrapolate on comorbidities associated with this phenotype and highlight clinical networks in the USA and Europe pursuing clinical research, concluding with funding efforts and recent recommendations to the NIH regarding DS research.

In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR). 5-PRA is extremely unstable under physiological conditions and is unlikely to accumulate in the absence of GART activity. Recently, a HeLa cell line null mutant for GART was constructed via CRISPR-Cas9 mutagenesis. This cell line, crGART, is likely an important cellular model of DNPS inactivation that does not accumulate DNPS pathway intermediates. In the current study, we characterize the crGART versus HeLa transcriptomes in purine-supplemented and purine-depleted growth conditions. We observed multiple transcriptome changes and discuss pathways and ontologies particularly relevant to Alzheimer disease and Down syndrome.

Amyotrophic lateral sclerosis (ALS) is a devastating disorder characterized by motor neuron apoptosis and subsequent skeletal muscle atrophy caused by oxidative and nitrosative stress, mitochondrial dysfunction, and neuroinflammation. Anthocyanins are polyphenolic compounds found in berries that possess neuroprotective and anti-inflammatory properties. Protocatechuic acid (PCA) is a phenolic acid metabolite of the parent anthocyanin, kuromanin, found in blackberries and bilberries. We explored the therapeutic effects of PCA in a transgenic mouse model of ALS that expresses mutant human Cu, Zn-superoxide dismutase 1 with a glycine to alanine substitution at position 93. These mice display skeletal muscle atrophy, hindlimb weakness, and weight loss. Disease onset occurs at approximately 90 days old and end stage is reached at approximately 120 days old. Daily treatment with PCA (100 mg/kg) by oral gavage beginning at disease onset significantly extended survival (121 days old in untreated vs. 133 days old in PCA-treated) and preserved skeletal muscle strength and endurance as assessed by grip strength testing and rotarod performance. Furthermore, PCA reduced astrogliosis and microgliosis in spinal cord, protected spinal motor neurons from apoptosis, and maintained neuromuscular junction integrity in transgenic mice. PCA lengthens survival, lessens the severity of pathological symptoms, and slows disease progression in this mouse model of ALS. Given its significant preclinical therapeutic effects, PCA should be further investigated as a treatment option for patients with ALS.

In de novo purine biosynthesis (DNPS), 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase (EC 2.1.2.3)/inosine monophosphate cyclohydrolase (EC 3.5.4.10) (ATIC) catalyzes the last two reactions of the pathway: conversion of 5-aminoimidazole-4-carboxamide ribonucleotide [aka Z-nucleotide monophosphate (ZMP)] to 5-formamido-4-imidazolecarboxamide ribonucleotide (FAICAR) then to inosine monophosphate (IMP). Mutations in ATIC cause an untreatable and devastating inborn error of metabolism in humans. ZMP is an adenosine monophosphate (AMP) mimetic and a known activator of AMP-activated protein kinase (AMPK). Recently, a HeLa cell line null mutant for ATIC was constructed via CRISPR-Cas9 mutagenesis. This mutant, crATIC, accumulates ZMP during purine starvation. Given that the mutant can accumulate ZMP in the absence of treatment with exogenous compounds, crATIC is likely an important cellular model of DNPS inactivation and ZMP accumulation. In the current study, we characterize the crATIC transcriptome versus the HeLa transcriptome in purine-supplemented and purine-depleted growth conditions. We report and discuss transcriptome changes with particular relevance to Alzheimer's disease and in genes relevant to lipid and fatty acid synthesis, neurodevelopment, embryogenesis, cell cycle maintenance and progression, extracellular matrix, immune function, TGFβ and other cellular processes.

AbstractBackgroundThe dysfunctional accumulation of amyloid beta (Aβ) plaques in neuronal cells is widely regarded as a hallmark sign of Alzheimer’s disease (AD). However, the mechanisms by which Aβ causes the rampant apoptosis that leads to the characteristic memory loss and dementia observed in AD patients are much less understood. In this study, we investigated the regulatory relationship between Aβ42, a particularly toxic member of the Aβ peptide family, and polyamines (PA), a ubiquitous class of molecules associated with cell growth, proliferation, and immune response. Increasing evidence has suggested that the PA pathway is changed in AD. For example, increased levels of enzymes in the PA synthesis pathway and altered PA metabolomics have been found in the AD brain. Here, we sought to investigate the relationship between PA synthesis and disease pathogenesis, specifically Aβ aggregation and in turn, neuronal death.MethodHT22 hippocampal cells were transiently transfected with bicistronic plasmids allowing for expression of DsRed alone or co‐expression with Aβ42. We then examined the effects of Aβ42 on expression of the rate limiting enzyme for PA synthesis, ornithine decarboxylase (ODC) and in turn, PA levels. Irreversible ODC inhibitor, L‐difluoromethylornithine (DFMO) was used to examine effects on Aβ42 aggregation and neuronal apoptosis. Hippocampal tissue from human sporadic AD and age matched controls were also assessed for PA concentration and ODC expression.ResultsWe found that Aβ42 increased PA levels in a dose‐dependent fashion through enhanced expression of ODC in HT22 hippocampal cells. Treatment with DFMO significantly reduced this increase in PA as well as aggregation of Aβ42 and Aβ42‐induced apoptosis. Lastly, levels of spermidine and spermine as well as ODC expression were significantly increased in sporadic AD human hippocampal tissue in comparison to age‐matched controls.ConclusionThese data suggest that increased intracellular concentrations of PA are not only a response to Aβ42, but they also promote Aβ42 toxicity by enhancing aggregation. Secondarily, DFMO may be a novel therapeutic to mitigate Aβ42 toxicity and reduce amyloid plaque load in patients with AD.

Amyloid beta (Aβ) is a cleavage product of amyloid precursor protein (APP) that is widely studied in Alzheimer's disease (AD) pathogenesis. There is increasing evidence for toxicity of another cleavage product, APP intracellular domain (AICD), which can be produced through both the amyloidogenic and nonamyloidogenic processing pathways. Current findings suggest that AICD produces neurotoxic effects principally through its nuclear function. However, there is a γ-secretase resident at the mitochondria, which could produce AICD locally within this organelle. Here, AICD-induced apoptosis was investigated in comparison to that induced by Aβ locally at the mitochondria. Hippocampal HT22 cells, primary hippocampal cells, and ρ0 cells which are devoid of mitochondrial DNA were transiently transfected with bicistronic plasmids containing DsRed and either empty vector IRES, Aβ, AICD, or mitochondrial targeted AICD (mitoAICD). Apoptosis of transfected cells was quantified using microscopy and examining nuclear morphology; cells with condensed and/or fragmented chromatin were considered apoptotic. In addition, the mechanisms by which the proteins induced apoptosis were investigated using transfected HT22 cells treated with either cyclosporin A (cyA) or pan-caspase inhibitor (casp) for inhibition of mitochondria permeability transition pore (mPTP) and caspases respectively. AICD alone did not induce significant apoptosis in comparison to that of the empty vector IRES in HT22 cells. However, when targeted to the mitochondria (mitoAICD), there was a significant increase in apoptosis like that induced by Aβ (Figure 1). Similar results were observed in primary hippocampal cultures. Further, apoptosis required functional mitochondria as neither Aβ nor mitoAICD induced significant levels of apoptosis in the ρ0 cells (Figure 2). Using the inhibitors, we found that cyA protects from Aβ, but not mitoAICD, while casp protected from mitoAICD, but not Aβ.

Adenylosuccinate lyase (ADSL) catalyzes two steps in de novo purine synthesis (DNPS). Mutations in ADSL can result in inborn errors of metabolism characterized by developmental delay and disorder phenotypes, with no effective treatment options. Recently, SAICAR, a metabolic substrate of ADSL, has been found to have alternative roles in the cell, complicating the role of ADSL. crADSL, a CRISPR KO of ADSL in HeLa cells, was constructed to investigate DNPS and ADSL in a human cell line. Here we employ this cell line in an RNA-seq analysis to initially investigate the effect of DNPS and ADSL deficiency on the transcriptome as a first step in establishing a cellular model of ADSL deficiency. We report transcriptome changes in genes relevant to development, vascular development, muscle, and cancer biology, which provide interesting avenues for future research.

Every person with Down syndrome (DS) has the characteristic features of Alzheimer's disease (AD) neuropathology in their brain by the age of forty, and most go on to develop AD dementia. Since people with DS show highly variable levels of baseline function, it is often difficult to identify early signs of dementia in this population. The discovery of blood biomarkers predictive of dementia onset and/or progression in DS is critical for developing effective clinical diagnostics. Our recent studies show that neuron-derived exosomes, which are small extracellular vesicles secreted by most cells in the body, contain elevated levels of amyloid-beta peptides and phosphorylated-Tau that could indicate a preclinical AD phase in people with DS starting in childhood. We also found that the relative levels of these biomarkers were altered following dementia onset. Exosome release and signaling are dependent on cellular redox homeostasis as well as on inflammatory processes, and exosomes may be involved in the immune response, suggesting a dual role as both triggers of inflammation in the brain and propagators of inflammatory signals between brain regions. Based on recently reported connections between inflammatory processes and exosome release, the elevated neuroinflammatory state observed in people with DS may affect exosomal AD biomarkers. Herein, we discuss findings from studies of people with DS, people with DS and AD (DS-AD), and mouse models of DS showing new connections between neuroinflammatory pathways, oxidative stress, exosomes, and exosome-mediated signaling, which may inform future AD diagnostics, preventions, and treatments in the DS population as well as in the general population.

We aim to establish that accelerated aging and premature cellular senescence seen in individuals with Down syndrome is related to reduced DNA polymeraseβ. We report here that primary fibroblasts from Down syndrome individuals exhibit greater SA-β-gal staining (fourfold increase, P  < 0.001), increased p16 transcript abundance (threefold increase, P  < 0.01), and reduced HMGB1 nuclear localization (1.5-fold lower, P  < 0.01). We also find that DNA polymerase β expression is significantly reduced in Down syndrome primary fibroblasts (53% decline, P  < 0.01). To evaluate whether DNA polymerase β might be causative in senescence induction, we evaluated the impact of murine DNA polymerase β nullizygosity on senescence. We find that unexposed DNA polymerase β -null primary fibroblasts exhibit a robust increase in the number of senescent cells compared to wild-type (11-fold, P  < 0.001), demonstrating that loss DNA polymerase β is sufficient to induce senescence. We also see an additional increase in response to hydroxyurea (threefold greater than WT-HU, P  < 0.05). These data demonstrate that loss of DNA polymerase β is sufficient to induce senescence. Additionally, we report a significant induction in spontaneous DNA double strand breaks in DNA polymerase β null MEFs (fivefold increase from wild-type, P  < 0.0001). Our findings strongly suggest that DNA polymerase β is causative in senescence induction, reasonably pointing to DNA polymerase β as a likely factor driving the premature senescence in Down syndrome. Environ. Mol. Mutagen. 59:603–612, 2018. © 2018 Wiley Periodicals, Inc.

We aim to establish that accelerated aging and premature cellular senescence seen in individuals with Down syndrome is related to reduced DNA polymeraseβ. We report here that primary fibroblasts from Down syndrome individuals exhibit greater SA‐β‐gal staining (fourfold increase, P < 0.001), increased p16 transcript abundance (threefold increase, P < 0.01), and reduced HMGB1 nuclear localization (1.5‐fold lower, P < 0.01). We also find that DNA polymerase β expression is significantly reduced in Down syndrome primary fibroblasts (53% decline, P < 0.01). To evaluate whether DNA polymerase β might be causative in senescence induction, we evaluated the impact of murine DNA polymerase β nullizygosity on senescence. We find that unexposed DNA polymerase β ‐null primary fibroblasts exhibit a robust increase in the number of senescent cells compared to wild‐type (11‐fold, P < 0.001), demonstrating that loss DNA polymerase β is sufficient to induce senescence. We also see an additional increase in response to hydroxyurea (threefold greater than WT‐HU, P < 0.05). These data demonstrate that loss of DNA polymerase β is sufficient to induce senescence. Additionally, we report a significant induction in spontaneous DNA double strand breaks in DNA polymerase β null MEFs (fivefold increase from wild‐type, P < 0.0001). Our findings strongly suggest that DNA polymerase β is causative in senescence induction, reasonably pointing to DNA polymerase β as a likely factor driving the premature senescence in Down syndrome. Environ. Mol. Mutagen. 59:603–612, 2018. © 2018 Wiley Periodicals, Inc.

Down syndrome (DS), caused by trisomy of chromosome 21, is the most common genetic cause of intellectual disability. Individuals with DS exhibit changes in neurochemistry and neuroanatomy that worsen with age, neurological delay in learning and memory, and predisposition to Alzheimer’s disease. The Ts65Dn mouse is the best characterized model of DS and has many features reminiscent of DS, including developmental anomalies and age-related neurodegeneration. The mouse carries a partial triplication of mouse chromosome 16 containing roughly 100 genes syntenic to human chromosome 21 genes. We hypothesized that there would be differences in brain metabolites with trisomy and age, and that long-term treatment with rapamycin, mechanistic target of rapamycin (mTOR) inhibitor and immunosuppressant, would correct these differences. Using HPLC coupled with electrochemical detection, we identified differences in levels of metabolites involved in dopaminergic, serotonergic, and kynurenine pathways in trisomic mice that are exacerbated with age. These include homovanillic acid, norepinephrine, and kynurenine. In addition, we demonstrate that prolonged treatment with rapamycin reduces accumulation of toxic metabolites (such as 6-hydroxymelatonin and 3-hydroxykynurenine) in aged mice.

This study was designed to investigate the brain proteome of the Ts65Dn mouse model of Down syndrome. We profiled the cerebellum and hippocampus proteomes of 6- and 12-month-old trisomic and disomic mice by difference gel electrophoresis. We quantified levels of 2082 protein spots and identified 272 (170 unique UniProt accessions) by mass spectrometry. Four identified proteins are encoded by genes trisomic in the Ts65Dn mouse. Three of these (CRYZL11, EZR, and SOD1) were elevated with p-value <0.05, and 2 proteins encoded by disomic genes (MAPRE3 and PHB) were reduced. Intergel comparisons based on age (6 vs. 12 months) and brain region (cerebellum vs. hippocampus) revealed numerous differences. Specifically, 132 identified proteins were different between age groups, and 141 identified proteins were different between the 2 brain regions. Our results suggest that compensatory mechanisms exist, which ameliorate the effect of trisomy in the Ts65Dn mice. Differences observed during aging may play a role in the accelerated deterioration of learning and memory seen in Ts65Dn mice.

Alzheimer’s disease is characterized by progressive memory loss, death of hippocampal, cortical pyramidal and basal forebrain cholinergic neurons, and formation of amyloid-beta (Aβ) plaques and neurofibrillary tangles. Neurotoxic fragments of amyloid-beta protein precursor (AβPP), such as Aβ1-42, are generated by amyloidogenic processing via βand γsecretases. However, recent findings suggest that full length AβPP is also toxic to neurons, although the mechanism by which the non-cleaved protein induces cell death is presently unclear. Here, we utilize a transient transfection strategy to show that overexpression of wild type (WT) AβPP in mouse hippocampal HT22 cells induces caspase-dependent apoptosis. Cell death induced by AβPP is independent of the mitochondrial permeability transition but requires the activation of Bax. Incubation with βor γ-secretase inhibitors has no effect on AβPP content or apoptosis and the mechanism of AβPP-induced cell death in HT22 cells is distinct from that of Aβ1-42 overexpression. Importantly, a mutant of AβPP that does not localize to mitochondria fails to induce apoptosis in HT22 cells. Finally, ρ0 SH-SY5Y neuroblastoma cells lacking functional mitochondria are resistant to AβPP-induced apoptosis. These findings demonstrate that the localization of full length AβPP to functional mitochondria is a prerequisite for this molecule to induce Bax-dependent apoptosis of hippocampal neuronal cells. Correspondence to: Dr. Daniel Linseman, Department of Biological Sciences, Eleanor Roosevelt Institute, and Knoebel Institute for Healthy Aging, University of Denver, 2199 S University Blvd, Denver, CO 80208; Tel: (303) 871-4663; Fax: (303) 871-3471; E-mail: daniel.linseman@du.edu

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 age-related 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.

A method for determining coordinate genetic regulation is proposed for mammalian cells. The method involves (i) isolation of a set of mutants defective in the relevant pathway; (ii) complementation analysis of these mutants to determine domi- nance and to categorize the mutants into various different comple- mentation groups; (iii) determination of the biochemical blocks in the mutants; (iv) identification of individual mutants that fail to complement the members of at least two distinct complementation groups that complement each other, such mutants being said to show coordinate regulation of the affected functions; (v) biochem- ical and reversion analysis of the relevant cell types to confirm the basis for the observed coordinate regulation; (vi) assignment of the individual genes to particular human chromosomes; (vii) mapping of the genes to determine contiguity on the genome; and (viii) ex- amination of the structure of the relevant gene products. This method has allowed the demonstration of coordinate regulation between the gene coding for phosphoribosylglycineamide synthe- tase (5-phosphoribosylamine:glycine ligase (ADP-forming), EC 6.3.4.13), defective in our Ade-C mutants, and the gene coding for phosphoribosylaminoimidazole synthetase (5'-phosphoribosylfor- mylglycinamidine cyclo-ligase (ADP-forming), EC 6.3.3.1), defec- tive in our Ade-G mutants. Moreover, both genes can be assigned to human chromosome 21. Because at least two genes for purine biosynthesis have now been assigned to chromosome 21, and be- cause patients with trisomy 21 (Down syndrome) show increased levels of serum purines, it may be that cells of these patients over- produce purines and that this overproduction may be relevant to the pathology of the syndrome. The organization of the genes coding for the enzymes of meta- bolic pathways in mammals is of fundamental interest. Such or- ganization is certain to be relevant to regulation of gene func- tion, yet little is known about this organization for enzymes in mammals. In certain cases, most notably the first three enzyme activities of pyrimidine biosynthesis, it has been possible to in- crease the levels of these three activities coordinately by gene amplification and to decrease these activities coordinately by mutation (1-3). Although the detailed organization and struc- ture of the DNA coding for these activities remain unclear, it is highly likely that the coding regions will be relatively close to each other because the three activities reside upon a single poly-

Down syndrome (DS) is a multifaceted genetic condition caused by the trisomy of chromosome 21. Cognitive impairment occurs invariably in DS. Individuals with DS are also highly susceptible to early-onset Alzheimer’s disease (AD). Longevity in DS patients has increased; however, this raises new challenges. Pharmacotherapeutic interventions that are safe, tolerable, and enhance cognitive functioning are crucial. Clinical trials in DS using approved interventions targeted for alleviating cognitive decline in AD have shown disappointing therapeutic effects. Despite promising studies from the Ts65Dn mouse model, corresponding translational efforts leading to clinical trials are far from robust. Additional studies are required to identify and validate drug candidates as well as increased efforts to define and conduct clinical trials. Investments of this type may well result in enhanced quality of life for children and adults with DS.