Innovating Therapies for Down Syndrome: An International Virtual Conference of the T21 Research Society.

Research focused on Down syndrome continued to gain momentum in the last several years and is advancing our understanding of how trisomy 21 (T21) modifies molecular and cellular processes. The Trisomy 21 Research Society (T21RS) is the premier scientific organization for researchers and clinicians studying Down syndrome. During the COVID pandemic, T21RS held its first virtual conference program, sponsored by the University of California at Irvine, on June 8-10, 2021 and brought together 342 scientists, families, and industry representatives from over 25 countries to share the latest discoveries on underlying cellular and molecular mechanisms of T21, cognitive and behavioral changes, and comorbidities associated with Down syndrome, including Alzheimer's disease and Regression Disorder. Presentations of 91 cutting-edge abstracts reflecting neuroscience, neurology, model systems, psychology, biomarkers, and molecular and pharmacological therapeutic approaches demonstrate the compelling interest and continuing advancement toward innovating biomarkers and therapies aimed at ameliorating health conditions associated with T21.

Basal forebrain atrophy along the Alzheimer's disease continuum in adults with Down syndrome.

BACKGROUND: Basal forebrain (BF) degeneration occurs in Down syndrome (DS)-associated Alzheimer's disease (AD). However, the dynamics of BF atrophy with age and disease progression, its impact on cognition, and its relationship with AD biomarkers have not been studied in DS. METHODS: We included 234 adults with DS (150 asymptomatic, 38 prodromal AD, and 46 AD dementia) and 147 euploid controls. BF volumes were extracted from T-weighted magnetic resonance images using a stereotactic atlas in SPM12. We assessed BF volume changes with age and along the clinical AD continuum and their relationship to cognitive performance, cerebrospinal fluid (CSF) and plasma amyloid/tau/neurodegeneration biomarkers, and hippocampal volume. RESULTS: In DS, BF volumes decreased with age and along the clinical AD continuum and significantly correlated with amyloid, tau, and neurofilament light chain changes in CSF and plasma, hippocampal volume, and cognitive performance. DISCUSSION: BF atrophy is a potentially valuable neuroimaging biomarker of AD-related cholinergic neurodegeneration in DS.

Genetic removal of synaptic Zn2+ impairs cognition, alters neurotrophic signaling and induces neuronal hyperactivity.

Vesicular Zn2+ (zinc) is released at synapses and has been demonstrated to modulate neuronal responses. However, mechanisms through which dysregulation of zinc homeostasis may potentiate neuronal dysfunction and neurodegeneration are not well-understood. We previously reported that accumulation of soluble amyloid beta oligomers (AßO) at synapses correlates with synaptic loss and that AßO localization at synapses is regulated by synaptic activity and enhanced by the release of vesicular Zn2+ in the hippocampus, a brain region that deteriorates early in Alzheimer's disease (AD). Significantly, drugs regulating zinc homeostasis inhibit AßO accumulation and improve cognition in mouse models of AD. We used both sexes of a transgenic mouse model lacking synaptic Zn2+ (ZnT3KO) that develops AD-like cognitive impairment and neurodegeneration to study the effects of disruption of Zn2+ modulation of neurotransmission in cognition, protein expression and activation, and neuronal excitability. Here we report that the genetic removal of synaptic Zn2+ results in progressive impairment of hippocampal-dependent memory, reduces activity-dependent increase in Erk phosphorylation and BDNF mRNA, alters regulation of Erk activation by NMDAR subunits, increases neuronal spiking, and induces biochemical and morphological alterations consistent with increasing epileptiform activity and neurodegeneration as ZnT3KO mice age. Our study shows that disruption of synaptic Zn2+ triggers neurodegenerative processes and is a potential pathway through which AßO trigger altered expression of neurotrophic proteins, along with reduced hippocampal synaptic density and degenerating neurons, neuronal spiking activity, and cognitive impairment and supports efforts to develop therapeutics to preserve synaptic zinc homeostasis in the brain as potential treatments for AD.

Repurposing cancer drugs identifies kenpaullone which ameliorates pathologic pain in preclinical models via normalization of inhibitory neurotransmission.

Inhibitory GABA-ergic neurotransmission is fundamental for the adult vertebrate central nervous system and requires low chloride concentration in neurons, maintained by KCC2, a neuroprotective ion transporter that extrudes intracellular neuronal chloride. To identify Kcc2 gene expression­enhancing compounds, we screened 1057 cell growth-regulating compounds in cultured primary cortical neurons. We identified kenpaullone (KP), which enhanced Kcc2/KCC2 expression and function in cultured rodent and human neurons by inhibiting GSK3ß. KP effectively reduced pathologic pain-like behavior in mouse models of nerve injury and bone cancer. In a nerve-injury pain model, KP restored Kcc2 expression and GABA-evoked chloride reversal potential in the spinal cord dorsal horn. Delta-catenin, a phosphorylation-target of GSK3ß in neurons, activated the Kcc2 promoter via KAISO transcription factor. Transient spinal over-expression of delta-catenin mimicked KP analgesia. Our findings of a newly repurposed compound and a novel, genetically-encoded mechanism that each enhance Kcc2 gene expression enable us to re-normalize disrupted inhibitory neurotransmission through genetic re-programming.

Building the Future Therapies for Down Syndrome: The Third International Conference of the T21 Research Society.

Research focused on Down syndrome has increased in the last several years to advance understanding of the consequences of trisomy 21 (T21) on molecular and cellular processes and, ultimately, on individuals with Down syndrome. The Trisomy 21 Research Society (T21RS) is the premier scientific organization for researchers and clinicians studying Down syndrome. The Third International Conference of T21RS, held June 6-9, 2019, in Barcelona, Spain, brought together 429 scientists, families, and industry representatives to share the latest discoveries on underlying cellular and molecular mechanisms of T21, define cognitive and behavioral challenges and better understand comorbidities associated with Down syndrome, including Alzheimer's disease and leukemia. Presentation of cutting-edge results in neuroscience, neurology, model systems, psychology, cancer, biomarkers and molecular and phar-ma-cological therapeutic approaches demonstrate the compelling interest and continuing advancement in all aspects of understanding and ameliorating conditions associated with T21.

Evolution of neuroinflammation across the lifespan of individuals with Down syndrome.

Epidemiological and experimental studies suggest that a disease-aggravating neuroinflammatory process is present at preclinical stages of Alzheimer's disease. Given that individuals with Down syndrome are at increased genetic risk of Alzheimer's disease and therefore develop the spectrum of Alzheimer's neuropathology in a uniform manner, they constitute an important population to study the evolution of neuroinflammation across the Alzheimer's continuum. Therefore, in this cross-sectional study, we characterized the brain inflammatory profile across the lifespan of individuals with Down syndrome. Microglial morphology and inflammatory cytokine expression were analysed by immunohistochemistry and electrochemiluminescent-based immunoassays in the frontal cortex from foetuses to adults with Down syndrome and control subjects (16 gestational weeks to 64 years), totalling 127 cases. Cytokine expression in mixed foetal primary cultures and hippocampus of adults with Down syndrome, as well as the effects of sex on cytokine expression were also analysed. A higher microglial soma size-to-process length ratio was observed in the frontal cortex of children and young adults with Down syndrome before the development of full-blown Alzheimer's pathology. Moreover, young adults with Down syndrome also displayed increased numbers of rod-like microglia. Increased levels of interleukin-8 and interleukin-10 were observed in children with Down syndrome (1-10 years; Down syndrome n = 5, controls n = 10) and higher levels of interleukin-1ß, interleukin-1α, interleukin-6, interleukin-8, interleukin-10, interleukin-15, eotaxin-3, interferon gamma-induced protein 10, macrophage-derived chemokine, and macrophage inflammatory protein-beta, were found in young adults with Down syndrome compared to euploid cases (13-25 years, Down syndrome n = 6, controls n = 24). Increased cytokine expression was also found in the conditioned media of mixed cortical primary cultures from second trimester foetuses with Down syndrome (Down syndrome n = 7, controls n = 7). Older adults with Down syndrome (39-68 years, Down syndrome n = 22, controls n = 16) displayed reduced levels of interleukin-10, interleukin-12p40, interferon-gamma and tumour necrosis factor-alpha. Microglia displayed larger somas and shorter processes. Moreover, an increase in dystrophic microglia and rod-like microglia aligning to neurons harbouring tau pathology were also observed. Sex stratification analyses revealed that females with Down syndrome had increased interleukin-6 and interleukin-8 levels compared to males with Down syndrome. Finally, multivariate projection methods identified specific cytokine patterns among individuals with Down syndrome. Our findings indicate the presence of an early and evolving neuroinflammatory phenotype across the lifespan in Down syndrome, a knowledge that is relevant for the discovery of stage-specific targets and for the design of possible anti-inflammatory trials against Alzheimer's disease in this population.

Suppressing Aneuploidy-Associated Phenotypes Improves the Fitness of Trisomy 21 Cells.

An abnormal number of chromosomes, or aneuploidy, accounts for most spontaneous abortions, causes developmental defects, and is associated with aging and cancer. The molecular mechanisms by which aneuploidy disrupts cellular function remain largely unknown. Here, we show that aneuploidy disrupts the morphology of the nucleus. Mutations that increase the levels of long-chain bases suppress nuclear abnormalities of aneuploid yeast independent of karyotype identity. Quantitative lipidomics indicates that long-chain bases are integral components of the nuclear membrane in yeast. Cells isolated from patients with Down syndrome also show that abnormal nuclear morphologies and increases in long-chain bases not only suppress these abnormalities but also improve their fitness. We obtained similar results with cells isolated from patients with Patau or Edward syndrome, indicating that increases in long-chain bases improve the fitness of aneuploid cells in yeast and humans. Targeting lipid biosynthesis pathways represents an important strategy to suppress nuclear abnormalities in aneuploidy-associated diseases.

Paving the Way for Therapy: The Second International Conference of the Trisomy 21 Research Society.

In the last decade, a number of important research advances in different fields have allowed Down syndrome (DS) research to flourish, creating a time of both unparalleled opportunity and considerable challenge. Building a scientific framework that distills mechanisms involved in the developmental intellectual disability of DS as well as the early-onset component of Alzheimer disease and the several other comorbidities associated with the condition is a challenge that scientists are now tackling using novel technologies and multidisciplinary approaches. The Trisomy 21 Research Society (T21RS) was founded in 2014 to address these evolving needs and challenges. In June of 2017, the T21RS held its 2nd International Conference in Chicago, USA. With more than 200 scientists, advocates, people with DS, and family members in attendance, the meeting served as a forum for the discussion of the latest research and clinical advances as well as the most compelling needs of people with DS and their families.

Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells.

Mounting evidence implicates chronic oxidative stress as a critical driver of the aging process. Down syndrome (DS) is characterized by a complex phenotype, including early senescence. DS cells display increased levels of reactive oxygen species (ROS) and mitochondrial structural and metabolic dysfunction, which are counterbalanced by sustained Nrf2-mediated transcription of cellular antioxidant response elements (ARE). Here, we show that caspase 3/PKCδdependent activation of the Nrf2 pathway in DS and Dp16 (a mouse model of DS) cells is necessary to protect against chronic oxidative damage and to preserve cellular functionality. Mitochondria-targeted catalase (mCAT) significantly reduced oxidative stress, restored mitochondrial structure and function, normalized replicative and wound healing capacity, and rendered the Nrf2-mediated antioxidant response dispensable. These results highlight the critical role of Nrf2/ARE in the maintenance of DS cell homeostasis and validate mitochondrial-specific interventions as a key aspect of antioxidant and antiaging therapies.

Dendritic spine pathology and thrombospondin-1 deficits in Down syndrome.

Abnormal dendritic spine structure and function is one of the most prominent features associated with neurodevelopmental disorders including Down syndrome (DS). Defects in both spine morphology and spine density may underlie alterations in neuronal and synaptic plasticity, ultimately affecting cognitive ability. Here we briefly examine the role of astrocytes in spine alterations and more specifically the involvement of astrocyte-secreted thrombospondin 1 (TSP-1) deficits in spine and synaptic pathology in DS.

Low Cost Electrode Assembly for EEG Recordings in Mice.

Wireless electroencephalography (EEG) of small animal subjects typically utilizes miniaturized EEG devices which require a robust recording and electrode assembly that remains in place while also being well-tolerated by the animal so as not to impair the ability of the animal to perform normal living activities or experimental tasks. We developed simple and fast electrode assembly and method of electrode implantation using electrode wires and wire-wrap technology that provides both higher survival and success rates in obtaining recordings from the electrodes than methods using screws as electrodes. The new wire method results in a 51% improvement in the number of electrodes that successfully record EEG signal. Also, the electrode assembly remains affixed and provides EEG signal for at least a month after implantation. Screws often serve as recording electrodes, which require either drilling holes into the skull to insert screws or affixing screws to the surface of the skull with adhesive. Drilling holes large enough to insert screws can be invasive and damaging to brain tissue, using adhesives may interfere with conductance and result in a poor signal, and soldering screws to wire leads results in fragile connections. The methods presented in this article provide a robust implant that is minimally invasive and has a significantly higher success rate of electrode implantation. In addition, the implant remains affixed and produces good recordings for over a month, while using economical, easily obtained materials and skills readily available in most animal research laboratories.

Metabolic and Growth Rate Alterations in Lymphoblastic Cell Lines Discriminate Between Down Syndrome and Alzheimer's Disease.

BACKGROUND: Deficits in mitochondrial function and oxidative stress play pivotal roles in Down syndrome (DS) and Alzheimer's disease (AD) and these alterations in mitochondria occur systemically in both conditions. OBJECTIVE: We hypothesized that peripheral cells of elder subjects with DS exhibit disease-specific and dementia-specific metabolic features. To test this, we performed a comprehensive analysis of energy metabolism in lymphoblastic-cell-lines (LCLs) derived from subjects belonging to four groups: DS-with-dementia (DSAD), DS-without-dementia (DS), sporadic AD, and age-matched controls. METHODS: LCLs were studied under regular or minimal feeding regimes with galactose or glucose as primary carbohydrate sources. We assessed metabolism under glycolysis or oxidative phosphorylation by quantifying cell viability, oxidative stress, ATP levels, mitochondrial membrane potential (MMP), mitochondrial calcium uptake, and autophagy. RESULTS: DS and DSAD LCLs showed slower growth rates under minimal feeding. DS LCLs mainly dependent on mitochondrial respiration exhibited significantly slower growth and higher levels of oxidative stress compared to other groups. While ATP levels (under mitochondrial inhibitors) and mitochondrial calcium uptake were significantly reduced in DSAD and AD cells, MMP was decreased in DS, DSAD, and AD LCLs. Finally, DS LCLs showed markedly reduced levels of the autophagy marker LC3-II, underscoring the close association between metabolic dysfunction and impaired autophagy in DS. CONCLUSION: There are significant mitochondrial functional changes in LCLs derived from DS, DSAD, and AD patients. Several parameters analyzed were consistently different between DS, DSAD, and AD lines suggesting that metabolic indicators between LCL groups may be utilized as biomarkers of disease progression and/or treatment outcomes.

Changing Paradigms in Down Syndrome: The First International Conference of the Trisomy 21 Research Society.

Down syndrome (DS) is the most common genetic cause of intellectual disability (ID) in humans with an incidence of ∼1:1,000 live births worldwide. It is caused by the presence of an extra copy of all or a segment of the long arm of human chromosome 21 (trisomy 21). People with DS present with a constellation of phenotypic alterations involving most organs and organ systems. ID is present in all people with DS, albeit with variable severity. DS is also the most frequent genetic cause of Alzheimer's disease (AD), and ∼50% of those with DS will develop AD-related dementia. In the last few years, significant progress has been made in understanding the crucial genotype-phenotype relationships in DS, in identifying the alterations in molecular pathways leading to the various clinical conditions present in DS, and in preclinical evaluations of potential therapies to improve the overall health and well-being of individuals with DS. In June 2015, 230 scientists, advocates, patients, and family members met in Paris for the 1st International Conference of the Trisomy 21 Research Society. Here, we report some of the most relevant presentations that took place during the meeting.

A Syntenic Cross Species Aneuploidy Genetic Screen Links RCAN1 Expression to ß-Cell Mitochondrial Dysfunction in Type 2 Diabetes.

Type 2 diabetes (T2D) is a complex metabolic disease associated with obesity, insulin resistance and hypoinsulinemia due to pancreatic ß-cell dysfunction. Reduced mitochondrial function is thought to be central to ß-cell dysfunction. Mitochondrial dysfunction and reduced insulin secretion are also observed in ß-cells of humans with the most common human genetic disorder, Down syndrome (DS, Trisomy 21). To identify regions of chromosome 21 that may be associated with perturbed glucose homeostasis we profiled the glycaemic status of different DS mouse models. The Ts65Dn and Dp16 DS mouse lines were hyperglycemic, while Tc1 and Ts1Rhr mice were not, providing us with a region of chromosome 21 containing genes that cause hyperglycemia. We then examined whether any of these genes were upregulated in a set of ~5,000 gene expression changes we had identified in a large gene expression analysis of human T2D ß-cells. This approach produced a single gene, RCAN1, as a candidate gene linking hyperglycemia and functional changes in T2D ß-cells. Further investigations demonstrated that RCAN1 methylation is reduced in human T2D islets at multiple sites, correlating with increased expression. RCAN1 protein expression was also increased in db/db mouse islets and in human and mouse islets exposed to high glucose. Mice overexpressing RCAN1 had reduced in vivo glucose-stimulated insulin secretion and their ß-cells displayed mitochondrial dysfunction including hyperpolarised membrane potential, reduced oxidative phosphorylation and low ATP production. This lack of ß-cell ATP had functional consequences by negatively affecting both glucose-stimulated membrane depolarisation and ATP-dependent insulin granule exocytosis. Thus, from amongst the myriad of gene expression changes occurring in T2D ß-cells where we had little knowledge of which changes cause ß-cell dysfunction, we applied a trisomy 21 screening approach which linked RCAN1 to ß-cell mitochondrial dysfunction in T2D.

Nerve growth factor metabolic dysfunction in Down's syndrome brains.

Basal forebrain cholinergic neurons play a key role in cognition. This neuronal system is highly dependent on NGF for its synaptic integrity and the phenotypic maintenance of its cell bodies. Basal forebrain cholinergic neurons progressively degenerate in Alzheimer's disease and Down's syndrome, and their atrophy contributes to the manifestation of dementia. Paradoxically, in Alzheimer's disease brains, the synthesis of NGF is not affected and there is abundance of the NGF precursor, proNGF. We have shown that this phenomenon is the result of a deficit in NGF's extracellular metabolism that compromises proNGF maturation and exacerbates its subsequent degradation. We hypothesized that a similar imbalance should be present in Down's syndrome. Using a combination of quantitative reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting and zymography, we investigated signs of NGF metabolic dysfunction in post-mortem brains from the temporal (n = 14), frontal (n = 34) and parietal (n = 20) cortex obtained from subjects with Down's syndrome and age-matched controls (age range 31-68 years). We further examined primary cultures of human foetal Down's syndrome cortex (17-21 gestational age weeks) and brains from Ts65Dn mice (12-22 months), a widely used animal model of Down's syndrome. We report a significant increase in proNGF levels in human and mouse Down's syndrome brains, with a concomitant reduction in the levels of plasminogen and tissue plasminogen activator messenger RNA as well as an increment in neuroserpin expression; enzymes that partake in proNGF maturation. Human Down's syndrome brains also exhibited elevated zymogenic activity of MMP9, the major NGF-degrading protease. Our results indicate a failure in NGF precursor maturation in Down's syndrome brains and a likely enhanced proteolytic degradation of NGF, changes which can compromise the trophic support of basal forebrain cholinergic neurons. The alterations in proNGF and MMP9 were also present in cultures of Down's syndrome foetal cortex; suggesting that this trophic compromise may be amenable to rescue, before frank dementia onset. Our study thus provides a novel paradigm for cholinergic neuroprotection in Alzheimer's disease and Down's syndrome.

Disruption of zinc neuromodulation by Aß oligomers: therapeutic implications.

So far, therapeutics focusing on reducing levels of amyloid beta for treatment of Alzheimer's disease have not been successful in completing clinical trials to come to market, suggesting the need of a wider perspective and the consideration of novel targets of intervention to slow or halt the progression of this disease. One such target is soluble amyloid beta in oligomeric forms, which have been demonstrated to bind with high affinity to zinc released during synaptic activity. This review considers the interaction of AßO and zinc and the role of zinc in neurotransmission along with possible neurotoxic effects of this interaction. Finally, it also discusses recent experimental data in animal models that have translated into potential treatments for AD based on the modulation of hyperexcitability and zinc homeostasis.

Dosage of amyloid precursor protein affects axonal contact guidance in Down syndrome.

Amyloid precursor protein (APP), encoded on Hsa21, functions as a cell adhesion molecule (CAM) in axonal growth cones (GCs) of the developing brain. We show here that axonal GCs of human fetal Down syndrome (DS) neurons (and of a DS mouse model) overexpress APP protein relative to euploid controls. We investigated whether DS neurons generate an abnormal, APP-dependent GC phenotype in vitro. On laminin, which binds APP and ß1 integrins (Itgb1), DS neurons formed enlarged and faster-advancing GCs compared to controls. On peptide matrices that bind APP only, but not on those binding exclusively Itgb1 or L1CAM, DS GCs were significantly enlarged (2.0-fold), formed increased close adhesions (1.8-fold), and advanced faster (1.4-fold). In assays involving alternating stripes of monospecific matrices, human control GCs exhibited no preference for any of the substrates, whereas DS GCs preferred the APP-binding matrix (cross-over decreased significantly from 48.2 to 27.2%). Reducing APP expression in DS GCs with siRNA normalized most measures of the phenotype, including substrate choice. These experiments show that human DS neurons exhibit an APP-dependent, abnormal GC phenotype characterized by increased adhesion and altered contact guidance. The results suggest that APP overexpression may perturb axonal pathfinding and circuit formation in developing DS brain.

Bisphenol A delays the perinatal chloride shift in cortical neurons by epigenetic effects on the Kcc2 promoter.

Bisphenol A (BPA) is a ubiquitous compound that is emerging as a possible toxicant during embryonic development. BPA has been shown to epigenetically affect the developing nervous system, but the molecular mechanisms are not clear. Here we demonstrate that BPA exposure in culture led to delay in the perinatal chloride shift caused by significant decrease in potassium chloride cotransporter 2 (Kcc2) mRNA expression in developing rat, mouse, and human cortical neurons. Neuronal chloride increased correspondingly. Treatment with epigenetic compounds decitabine and trichostatin A rescued the BPA effects as did knockdown of histone deacetylase 1 and combined knockdown histone deacetylase 1 and 2. Furthermore, BPA evoked increase in tangential interneuron migration and increased chloride in migrating neurons. Interestingly, BPA exerted its effect in a sexually dimorphic manner, with a more accentuated effect in females than males. By chromatin immunoprecipitation, we found a significant increase in binding of methyl-CpG binding protein 2 to the "cytosine-phosphate-guanine shores" of the Kcc2 promoter, and decrease in binding of acetylated histone H3K9 surrounding the transcriptional start site. Methyl-CpG binding protein 2-expressing neurons were more abundant resulting from BPA exposure. The sexually dimorphic effect of BPA on Kcc2 expression was also demonstrated in cortical neurons cultured from the offspring of BPA-fed mouse dams. In these neurons and in cortical slices, decitabine was found to rescue the effect of BPA on Kcc2 expression. Overall, our results indicate that BPA can disrupt Kcc2 gene expression through epigenetic mechanisms. Beyond increase in basic understanding, our findings have relevance for identifying unique neurodevelopmental toxicity mechanisms of BPA, which could possibly play a role in pathogenesis of human neurodevelopmental disorders.

Adaptive downregulation of mitochondrial function in down syndrome.

Mitochondrial dysfunction and oxidative stress are common features of Down syndrome (DS). However, the underlying mechanisms are not known. We investigated the relationship between abnormal energy metabolism and oxidative stress with transcriptional and functional changes in DS cells. Impaired mitochondrial activity correlated with altered mitochondrial morphology. Increasing fusion capacity prevented morphological but not functional alterations in DS mitochondria. Sustained stimulation restored mitochondrial functional parameters but increased reactive oxygen species production and cell damage, suggesting that reduced DS mitochondrial activity is an adaptive response for avoiding injury and preserving basic cellular functions. Network analysis of genes overexpressed in DS cells demonstrated functional integration in pathways involved in energy metabolism and oxidative stress. Thus, although preventing extensive oxidative damage, mitochondrial downregulation may contribute to increased susceptibility of individuals with DS to clinical conditions in which altered energy metabolism may play a role, such as Alzheimer's disease, diabetes, and some types of autistic spectrum disorders.

Oxidative Stress and Mitochondrial Dysfunction in Down's Syndrome: Relevance to Aging and Dementia.

Genome-wide gene deregulation and oxidative stress appear to be critical factors determining the high variability of phenotypes in Down's syndrome (DS). Even though individuals with trisomy 21 exhibit a higher survival rate compared to other aneuploidies, most of them die in utero or early during postnatal life. While the survivors are currently predicted to live past 60 years, they suffer higher incidence of age-related conditions including Alzheimer's disease (AD). This paper is centered on the mechanisms by which mitochondrial factors and oxidative stress may orchestrate an adaptive response directed to maintain basic cellular functions and survival in DS. In this context, the timing of therapeutic interventions should be carefully considered for the successful treatment of chronic disorders in the DS population.