Down Syndrome Individuals Research Articles

Expression Profiling of Notch Signalling Pathway and Gamma-Secretase Activity in the Brain of Ts1Cje Mouse Model of Down Syndrome.

Notch signalling pathway is involved in the proliferation of neural progenitor cells (NPCs), to inhibit neuronal cell commitment and to promote glial cell fate. Notch protein is cleaved by gamma-secretase, a multisubunit transmembrane protein complex that releases the Notch intracellular domain (NICD) and subsequently activates the downstream targets. Down syndrome (DS) individuals exhibit an increased number of glial cells (particularly astrocytes), and reduced number of neurons suggesting the involvement of Notch signalling pathway in the neurogenic-to-gliogenic shift in DS brain. Ts1Cje is a DS mouse model that exhibit similar neuropathology to human DS individuals. To date, the spatiotemporal gene expression of the Notch and gamma-secretase genes have not been characterised in Ts1Cje mouse brain. Understanding the expression pattern of Notch and gamma-secretase genes may provide a better understanding of the underlying mechanism that leads to the shift. Gene expression analysis using RT-qPCR was performed on early embryonic and postnatal development of DS brain. In the developing mouse brain, mRNA expression analysis showed that gamma-secretase members (Psen1, Pen-2, Aph-1b, and Ncstn) were not differentially expressed. Notch2 was found to be downregulated in the developing Ts1Cje brain samples. Postnatal gene expression study showed complex expression patterns and Notch1 and Notch2 genes were found to be significantly downregulated in the hippocampus at postnatal day 30. Results from RT-qPCR analysis from E15.5 neurosphere culture showed an increase of expression of Psen1, and Aph-1b but downregulation of Pen-2 and Ncstn genes. Gamma-secretase activity in Ts1Cje E15.5 neurospheres was significantly increased by fivefold. In summary, the association and the role of Notch and gamma-secretase gene expression throughout development with neurogenic-to-gliogenic shift in Ts1Cje remain undefined and warrant further validation.

Social Cognition in Down Syndrome: Face Tuning in Face-Like Non-Face Images.

Individuals with Down syndrome (DS) are widely believed to possess considerable socialization strengths. However, the findings on social cognition capabilities are controversial. In the present study, we investigated whether individuals with DS exhibit shortage in face tuning, one of the indispensable components of social cognition. For this purpose, we implemented a recently developed Face-n-Food paradigm with food-plate images composed of food ingredients such as fruits and vegetables. The key benefit of such face-like non-face images is that single elements do not facilitate face processing. In a spontaneous recognition task, 25 children with DS aged 9 to 18 years were presented with a set of Face-n-Food images bordering on the Giuseppe Arcimboldo style. The set of images was administered in a predetermined order from the least to most resembling a face. In DS individuals, thresholds for recognition of the Face-n-Food images as a face were drastically higher as compared not only with typically developing controls, but also with individuals with autistic spectrum disorders and Williams-Beuren syndrome. This outcome represents a significant step toward better conceptualization of the visual social world in DS and neurodevelopmental disorders in general.

324 - Investigation of cytoplasmic and mitochondrial redox status in Down syndrome: impact of the thioredoxin and glutathione systems

Down syndrome (DS) results from the triplication of whole or part of chromosome 21. Individuals with DS experience a variety of comorbidities at a higher rate than the euploid population, and many of these pathologies involve oxidative stress as an etiological factor. Blood and postmortem tissue samples from DS individuals indicate elevated basal levels of oxidative stress, potentially due to mitochondrial dysfunction. Due to these observations we hypothesized that cells from DS individuals would display greater basal oxidation in the cytoplasmic and mitochondrial compartments, and that manipulation of the thioredoxin (Trx) or glutathione (GSH) systems would exacerbate this oxidation. To investigate this, we employed four pairs of patient-derived euploid or DS fibroblasts, and utilized auranofin or BSO to selectively modulate the Trx and GSH systems, respectively. Additionally, peroxiredoxin (Prx) redox Western blots were used to assess cytoplasmic (Prx1) and mitochondrial (Prx3) redox status. Results from these studies showed that inhibition of the Trx system via auranofin induced significant oxidation of both cytoplasmic and mitochondrial compartments. Interestingly, depletion of GSH by BSO did not cause significant oxidation of either Prx1 or Prx3 in DS vs. euploid controls. Mechanistically, increased sensitivity in compartmental oxidation observed in DS may be explained by our observation of significantly decreased protein levels of thioredoxin reductase (TrxR) 1 and 2, as well as significantly decreased TrxR activity in DS. Together, these data indicate that DS individuals may be highly susceptible to exposures or treatments known to oxidize the thiol redox proteome, thereby enhancing the risk of initiation and progression of DS-related comorbidities.

Restoring microglial and astroglial homeostasis using DNA immunization in a Down Syndrome mouse model

Down Syndrome (DS), the most common cause of genetic intellectual disability, is characterized by over-expression of the APP and DYRK1A genes, located on the triplicated chromosome 21. This chromosomal abnormality leads to a cognitive decline mediated by Amyloid-β (Aβ) overproduction and tau hyper-phosphorylation as early as the age of 40.In this study, we used the Ts65Dn mouse model of DS to evaluate the beneficial effect of a DNA vaccination against the Aβ1-11 fragment, in ameliorating Aβ-related neuropathology and rescue of cognitive and behavioral abilities. Anti-Aβ1-11 vaccination induced antibody production and facilitated clearance of soluble oligomers and small extracellular inclusions of Aβ from the hippocampus and cortex of Ts65Dn mice. This was correlated with reduced neurodegeneration and restoration of the homeostatic phenotype of microglial and astroglial cells. Vaccinated Ts65Dn mice performed better in spatial-learning tasks, exhibited reduced motor hyperactivity typical for this strain, and restored short-term memory abilities.Our findings support the hypothesis that DS individuals may benefit from active immunotherapy against Aβ from a young age by slowing the progression of dementia.

Evaluation of Reactive Oxygen Metabolites in Down Syndrome Persons With Periodontitis— A Comparative Study

Down syndrome (DS) is one of the most common chromosomal disorders, occurring in one out of 700-1000 live births, and the most common cause of mental retardation. Increasing evidence has shown that DS individuals are under unusual increased oxidative stress, which may be involved in the higher prevalence and severity of a number of pathologies associated with the syndrome, as well as the accelerated ageing observed in these individuals. ROS leads to oxidative damage of DNA, proteins and lipids; therefore, oxidative stress may play an important role in the pathogenesis of DS. Periodontal disease is a common problem among DS individuals. The disease starts early in life and progresses with age eventually leading to tooth loss. This study was undertaken to evaluate and compare the levels of ROM in DS subjects with periodontitis and systemically healthy subjects with chronic periodontitis. There is significant increase in levels of ROM and shows statistically significant value (<0.001) in DS with Chronic periodontitis patients.

Expressed emotion and impulsiveness in mothers of children with Fragile X Syndrome and Down Syndrome: The relation to behavioral problems in their offspring

BackgroundFragile X Syndrome (FXS) and Down Syndrome (DS) are common causes of Intellectual Disability (ID). Mothers of individuals with FXS sometimes have the premutation condition which makes them display neurocognitive signs, such as impulsiveness impairments, while mothers of DS individuals, as a group, do not have impairments. Although behavior problems in individuals with ID may be related to high Expressed Emotion (EE) in parents, parenting in families with ID members has been little explored. AimTo explore the relationship between a mother’s EE and impulsiveness, in mothers of individuals with FXS and DS, with behavior problems in their offspring. MethodA questionnaire was developed to collect data about impulsiveness and EE in mothers, along with information about behavior problems in ID individuals. ResultsEE scores were associated with behavior problems in their offspring for both samples. Mothers with the premutation showed higher scores in EE than mothers of DS individuals. However, impulsiveness scores were not different between both parental groups, and were related to EE scores. ConclusionsEE is a parental feature that is possible to modulate and seems to be related to behavior problems in ID individuals. More research should be carried on to create interventions to reduce this attitude in parents of ID individuals.

Transcriptomic profiling of skeletal muscle from the Ts1Cje mouse model of Down syndrome suggests dysregulation of trisomic genes associated with neuromuscular junction signaling, oxidative stress and chronic inflammation

Ts1Cje is a mouse model of Down syndrome (DS) with partial triplication of chromosome 16, which encompasses a high number of human chromosome 21 (HSA21) orthologous genes. The mouse model exhibits muscle weakness resembling hypotonia in DS individuals. The effect of extra gene dosages on muscle weakness or hypotonia in Ts1Cje and DS individuals remains unknown. To identify molecular dysregulation of the skeletal muscle, we compared the transcriptomic signatures of soleus and extensor digitorum longus (EDL) muscles between the adult Ts1Cje and disomic littermates. A total of 166 and 262 differentially expressed protein-coding genes (DEGs) were identified in the soleus and EDL muscles, respectively. The partial trisomy of MMU16 in Ts1Cje mice has a greater effect on gene expression in EDL. Top-down clustering analysis of all DEGs for represented functional ontologies revealed 5 functional clusters in soleus associated with signal transduction, development of reproductive system, nucleic acid biosynthesis, protein modification and metabolism as well as regulation of gene expression. On the other hand, only 3 functional clusters were observed for EDL namely neuron and cell development, protein modification and metabolic processes as well as ion transport. A total of 11 selected DEGs were validated using qPCR (disomic DEGs: Mansc1; trisomic DEGs: Itsn1, Rcan1, Synj1, Donson, Dyrk1a, Ifnar1, Ifnar2, Runx1, Sod1 and Tmem50b). The validated DEGs were implicated in neuromuscular junction signalling (Itsn1, Syn1), oxidative stress (Sod1, Runx1) and chronic inflammation processes (Runx1, Rcan1, Ifnar1, Ifnar2). Other validated DEGs have not been well-documented as involved in the skeletal muscle development or function, thus serve as interesting novel candidates for future investigations. To our knowledge, the study was the first attempt to determine the transcriptomic profiles of both soleus and EDL muscles in Ts1Cje mice. It provides new insights on the possible disrupted molecular pathways associated with hypotonia in DS individuals.

Interleukin 6 and 10 Serum Levels and Genetic Polymorphisms in Children with Down Syndrome.

Immunological impairment is a condition that is often observed in individuals with Down syndrome (DS). The immune response is modulated by pro- and anti-inflammatory cytokines whose expressions could be influenced by genetic polymorphisms. The present study was aimed at evaluating the frequencies of -174G>C, -572G>C, and -597G>A polymorphisms in the interleukin 6 (IL-6) gene and -592C>A, -1082A>G, and -819C>T polymorphisms in the IL-10 gene and the IL-6 and IL-10 serum levels in healthy individuals with and without DS. The authors also aimed to investigate the impact of the genotypes on the interleukin concentrations. The genetic polymorphisms were investigated in 200 DS individuals and 200 controls without DS. The serum measurement of IL-6 and IL-10 was performed in a subgroup (54 cases and 54 controls) by enzyme-linked immunosorbent assay (ELISA). The frequencies of the polymorphisms and haplotypes evaluated were not different between individuals with and without DS. IL-10 concentration was higher in DS children but was not influenced by IL-10 gene polymorphisms. IL-6 genotypes had no influence on IL-6 serum levels. The IL-10 serum levels are increased in DS individuals, but IL-10 polymorphisms are not the main factors that influence the IL-10 expression in DS.

Prevalence of Aging, Dementia, and Multimorbidity in Older Adults With Down Syndrome

ImportanceAs the life expectancy of people with Down syndrome (DS) has markedly increased over the past decades, older adults with DS may be experiencing a higher incidence of aging conditions. In addition to longevity, the amyloid precursor protein gene located on chromosome 21 places individuals with DS at a high risk for developing Alzheimer disease. Yet, few studies have determined prevalence of dementia and comorbidities among older people with DS.ObjectiveTo determine the prevalence of dementia and aging-related comorbidities in older adult individuals with DS.Design, Setting, and ParticipantsCross-sectional analysis of 2015 California Medicare claims data. We examined 1 year of cross-sectional Medicare claims data that included 100% of Californian Medicare beneficiaries enrolled in both Medicare Part A and B in 2015. Of these 3 001 977 Californian Medicare beneficiaries 45 years or older, 878 individuals were identified as having a diagnosis of DS. Data were analyzed between April 2017 and February 2018.Main Outcomes and MeasuresThe frequency of DS dementia was assessed across different age categories. The number and frequency of 27 comorbidities were compared among individuals with DS with and without dementia and by age and sex groups.ResultsA total of 353 DS individuals (40%) were identified as having dementia diagnoses (mean, 58.7 years; 173 women [49%]) and 525 without dementia diagnoses (mean, 55.9 years; 250 women [48%]). The frequency of DS dementia among those 65 years or older rose to 49%. The mean number of comorbidities per individual increased with age in general. Comorbid conditions were more numerous among those with dementia compared with those with DS without dementia (mean, 3.4 vs 2.5, respectively), especially among those younger than 65 years. In particular, 4 treatable conditions, hypothyroidism, epilepsy, anemia, and weight loss, were much more frequent in DS dementia.Conclusions and RelevanceOlder Medicare beneficiaries in California with DS, especially those with dementia, have a high level of multimorbidity including several treatable conditions. While DS follow-up has long been confined to the pediatric sphere, we found that longevity in individuals with DS will necessitate complex adult and geriatric care. More evidenced-based and standardized follow-up could support better long-term comorbidity management and dementia care among aging adults with DS.

P.113 Down Syndrome: robust neurophysiological perspectives

Background: Down Syndrome (DS) has a mosaicism of presentations, but a number of common features. Cerebral evoked potentials (somatosensory, visual and auditory) can be higher in amplitude in DS. The aim of this study is to explore the value of the neurophysiological amplitude of three different modalities in DS individuals undergoing spinal surgery, or epilepsy evaluation. Methods: Standard procedure of EEG evaluation was conducted. We routinely monitor somatosensory (SSEP) and motor evoked potentials (MEP), using peripheral nerves stimulation and transcranial electrical stimulation during surgery. We report findings from 14 DS individuals age-matched to 14 individuals with idiopathic scoliosis Results: The amplitude of the SSEP is significantly higher in DS individuals than in age-matched controls using the same parameters. SSEP;10.2±2.5µV vs 2.4±2.3µV (p<0.05, paired t-test). The threshold for eliciting MEPs was also significantly lower in DS in comparison to controls, 175±20V vs 629±100V, (p<0.05, paired t-test). Interictal EEG showed high amplitude spike and waves, and greater intracortical coherence in DS with epilepsy than non-DS patients Conclusions: Robust neurophysiological findings showed high amplitude sensory evoked potentials, low threshold motor evoked potentials, and high amplitude spikes and wave, all reflect a common process of increased neuronal synchronicity and oscillatory behaviour in Down Syndrome.

Anti-IL17 treatment ameliorates Down syndrome phenotypes in mice

Down syndrome (DS) is characterized by structural and functional anomalies that are present prenatally and that lead to intellectual disabilities. Later in life, the cognitive abilities of DS individuals progressively deteriorate due to the development of Alzheimer’s disease (AD)-associated neuropathology (i.e., β-amyloid (Aβ) plaques, neurofibrillary tangles (NFTs), neurodegeneration, synaptic pathology, neuroinflammation and increased oxidative stress). Increasing evidence has shown that among these pathological processes, neuroinflammation plays a predominant role in AD etiopathology. In AD mouse models, increased neuroinflammation appears earlier than Aβ plaques and NFTs, and in DS and AD models, neuroinflammation exacerbates the levels of soluble and insoluble Aβ species, favoring neurodegeneration. The Ts65Dn (TS) mouse, the most commonly used murine model of DS, recapitulates many alterations present in both DS and AD individuals, including enhanced neuroinflammation. In this study, we observed an altered neuroinflammatory milieu in the hippocampus of the TS mouse model. Pro-inflammatory mediators that were elevated in the hippocampus of this model included pro-inflammatory cytokine IL17A, which has a fundamental role in mediating brain damage in neuroinflammatory processes. Here, we analyzed the ability of an anti-IL17A antibody to reduce the neuropathological alterations that are present in TS mice during early neurodevelopmental stages (i.e., hippocampal neurogenesis and hypocellularity) or that are aggravated in later-life stages (i.e., cognitive abilities, cholinergic neuronal loss and increased cellular senescence, APP expression, Aβ peptide expression and neuroinflammation). Administration of anti-IL17 for 5 months, starting at the age of 7 months, partially improved the cognitive abilities of the TS mice, reduced the expression of several pro-inflammatory cytokines and the density of activated microglia and normalized the APP and Aβ1–42 levels in the hippocampi of the TS mice. These results suggest that IL17-mediated neuroinflammation is involved in several AD phenotypes in TS mice and provide a new therapeutic target to reduce these pathological characteristics.

Early and Selective Activation and Subsequent Alterations to the Unfolded Protein Response in Down Syndrome Mouse Models.

Down syndrome (DS) is the most common chromosomal disorder and the leading genetic cause of intellectual disability in humans, which results from the triplication of chromosome 21. DS individuals have an increased risk of developing Alzheimer's disease (AD)-like pathology and dementia by the age of 40 due to the triplication of several genes involved in the formation of amyloid plaques and tau tangles. Further, DS and AD are characterized by the aberrant accumulation of unfolded/misfolded proteins resulting from over-burdened protein quality control systems. The accumulation of misfolded proteins in the endoplasmic reticulum (ER) triggers a cellular stress response called the unfolded protein response (UPR). Long-term activation of the UPR mediates neuronal dysfunction in AD. We hypothesized that the UPR is impacted in a mouse model of DS. To test this, we performed gene and protein expression analysis of ER stress markers in the Ts65Dn mouse model of DS at 3, 9, and 18 months. We identified activation of the PERK pathway in Ts65Dn DS mice at 3 months of age compared to euploid controls. We also determined that the early and overt UPR activation decreased with age, the UPR signal was significantly reduced by 18 months. Our data suggest that UPR activation in DS mouse models occurs early before consistent brain neurodegeneration and might be an essential contributor to dys-proteostasis.

Inflammatory biomarkers and intellectual disability in patients with Down syndrome.

Intellectual disability (ID) is part of the Down syndrome (DS) phenotypic spectrum, but the exact molecular pathophysiology of ID in individuals with DS is not yet fully understood, with many research hypotheses still unproven. Basing on previous studies (which suggested a possible role of altered inflammatory response in DS-related ID), we assessed the serum levels of a number of inflammatory biomarkers [serum amyloid A (SAA), C-reactive protein (C-RP), high mobility group box-1 (HMGB1)] in a cohort of individuals with DS and healthy controls. In total, 24 children diagnosed with DS and 12 healthy controls were enrolled, and all underwent detailed cognitive assessment. Also, serum SAA, C-RP and HMGB1 levels were measured in all recruited subjects and correlated to the severity of ID in the DS group. Serum SAA, C-RP and HMGB1 values were found to be significantly higher in the DS group compared with the healthy subjects (P=0.001). In addition, serum HMGB1 levels positively correlated with C-RP and SAA in the DS group but not in the healthy controls. Only serum C-RP levels resulted inversely correlated (P<0.01) with intelligence quotient (IQ); conversely, significant statistical correlations between serum SAA levels and IQ (as well as between HMGB1 and IQ) have been not found (P>0.05). The levels of the determined markers were higher in DS individuals compared with (cognitively) healthy subjects, and CRP showed a negative correlation with IQ in children with DS.

Reassessment of fluctuating dental asymmetry in Down syndrome

Fluctuating dental asymmetry (FDA) is a tool to measure developmental stability that could be increased in gonosomal aneuploidies. The aim of this study was to quantify FDA in individuals with Down syndrome (DS). The study group comprised 40 individuals with DS, and a control group matched for age and sex was created. The target teeth were the maxillary central incisors (11,21), maxillary lateral incisors (12,22), maxillary canines (13,23), and maxillary first molars (16,26). Dental morphometric variables measured on CBCT images included tooth length, crown height, root length, mesio-distal diameter, crown-to-root ratio, vestibular-palatine diameter, mid mesio-distal diameter, mid buccal-palatal diameter, maximum buccal-palatal diameter, and cervical circumference. The FA2 fluctuating asymmetry index (Palmer and Strobeck, 1986) was applied. Some discrepancies in crown-to-root ratios and root length asymmetry were significantly lower in the DS individuals than in controls. Combining the crown-to-root ratio of tooth 11 versus 21, tooth 12 versus 22, and tooth 13 versus 23, we developed a predictive model with a discriminatory power between DS and controls of 0.983. Some dental morphometric variables may actually be more stable in DS individuals than in the general population. This offers a new perspective on the relationship between canalization, fluctuating asymmetry, and aneuploidy.

Systematic proteome and proteostasis profiling in human Trisomy 21 fibroblast cells

Down syndrome (DS) is mostly caused by a trisomy of the entire Chromosome 21 (Trisomy 21, T21). Here, we use SWATH mass spectrometry to quantify protein abundance and protein turnover in fibroblasts from a monozygotic twin pair discordant for T21, and to profile protein expression in 11 unrelated DS individuals and matched controls. The integration of the steady-state and turnover proteomic data indicates that protein-specific degradation of members of stoichiometric complexes is a major determinant of T21 gene dosage outcome, both within and between individuals. This effect is not apparent from genomic and transcriptomic data. The data also reveal that T21 results in extensive proteome remodeling, affecting proteins encoded by all chromosomes. Finally, we find broad, organelle-specific post-transcriptional effects such as significant downregulation of the mitochondrial proteome contributing to T21 hallmarks. Overall, we provide a valuable proteomic resource to understand the origin of DS phenotypic manifestations.

Increased levels of inflammatory plasma markers and obesity risk in a mouse model of Down syndrome.

Down syndrome (DS) is caused by the trisomy of human chromosome 21 and is the most common genetic cause of intellectual disability. In addition to the intellectual deficiencies and physical anomalies, DS individuals present a higher prevalence of obesity and subsequent metabolic disorders than healthy adults. There is increasing evidence from both clinical and experimental studies indicating the association of visceral obesity with a pro-inflammatory status and recent studies have reported that obese people with DS suffer from low-grade systemic inflammation. However, the link between adiposity and inflammation has not been explored in DS. Here we used Ts65Dn mice, a validated DS mouse model, for the study of obesity-related inflammatory markers. Ts65Dn mice presented increased energy intake, and a positive energy balance leading to increased adiposity (fat mass per body weight), but did not show overweight, which only was apparent upon high fat diet induced obesity. Trisomic mice also had fasting hyperglycemia and hypoinsulinemia, and normal incretin levels. Those trisomy-associated changes were accompanied by reduced ghrelin plasma levels and slightly but not significantly increased leptin levels. Upon a glucose load, Ts65Dn mice showed normal increase of incretins accompanied by over-responses of leptin and resistin, while maintaining the hyperglycemic and hypoinsulinemic phenotype. These changes in the adipoinsular axis were accompanied by increased plasma levels of inflammatory biomarkers previously correlated with obesity galectin-3 and HSP72, and reduced IL-6. Taken together, these results suggest that increased adiposity, and pro-inflammatory adipokines leading to low-grade inflammation are important players in the propensity to obesity in DS. We conclude that DS would be a case of impaired metabolic-inflammatory axis.

The Influence of trisomy 21 on facial form and variability.

Triplication of chromosome 21 (trisomy 21) results in Down syndrome (DS), the most common live-born human aneuploidy. Individuals with DS have a unique facial appearance that can include form changes and altered variability. Using 3D photogrammatic images, 3D coordinate locations of 20 anatomical landmarks, and Euclidean Distance Matrix Analysis methods, we quantitatively test the hypothesis that children with DS (n = 55) exhibit facial form and variance differences relative to two different age-matched (4-12 years) control samples of euploid individuals: biological siblings of individuals with DS (n = 55) and euploid individuals without a sibling with DS (n = 55). Approximately 36% of measurements differ significantly between DS and DS-sibling samples, whereas 46% differ significantly between DS and unrelated control samples. Nearly 14% of measurements differ significantly in variance between DS and DS sibling samples, while 18% of measurements differ significantly in variance between DS and unrelated euploid control samples. Of those measures that showed a significant difference in variance, all were relatively increased in the sample of DS individuals. These results indicate that faces of children with DS are quantitatively more similar to their siblings than to unrelated euploid individuals and exhibit consistent, but slightly increased variation with most individuals falling within the range of normal variation established by euploid samples. These observations provide indirect evidence of the strength of the genetic underpinnings of the resemblance between relatives and the resistance of craniofacial development to genetic perturbations caused by trisomy 21, while underscoring the complexity of the genotype-phenotype map.

Quantification of plasma phosphorylated tau to use as a biomarker for brain Alzheimer pathology: pilot case-control studies including patients with Alzheimer\u2019s disease and down syndrome

BackgroundThere is still a substantial unmet need for less invasive and lower-cost blood-based biomarkers to detect brain Alzheimer’s disease (AD) pathology. This study is aimed to determine whether quantification of plasma tau phosphorylated at threonine 181 (p-tau181) is informative in the diagnosis of AD.MethodsWe have developed a novel ultrasensitive immunoassay to quantify plasma p-tau181, and measured the levels of plasma p-tau181 in three cohorts.ResultsIn the first cohort composed of 20 AD patients and 15 age-matched controls, the plasma levels of p-tau181 were significantly higher in the AD patients than those in the controls (0.171 ± 0.166 pg/ml in AD versus 0.0405 ± 0.0756 pg/ml in controls, p = 0.0039). The percentage of the subjects whose levels of plasma p-tau181 exceeded the cut-off value (0.0921 pg/ml) was significantly higher in the AD group compared with the control group (60% in AD versus 16.7% in controls, p = 0.0090). In the second cohort composed of 20 patients with Down syndrome (DS) and 22 age-matched controls, the plasma concentrations of p-tau181 were significantly higher in the DS group (0.767 ± 1.26 pg/ml in DS versus 0.0415 ± 0.0710 pg/ml in controls, p = 0.0313). There was a significant correlation between the plasma levels of p-tau181 and age in the DS group (R2 = 0.4451, p = 0.0013). All of the DS individuals showing an extremely high concentration of plasma p-tau181 (> 1.0 pg/ml) were older than the age of 40. In the third cohort composed of 8 AD patients and 3 patients with other neurological diseases, the levels of plasma p-tau181 significantly correlated with those of CSF p-tau181 (R2 = 0.4525, p = 0.023).ConclusionsWe report for the first time quantitative data on the plasma levels of p-tau181 in controls and patients with AD and DS, and these data suggest that the plasma p-tau181 is a promising blood biomarker for brain AD pathology. This exploratory pilot study warrants further large-scale and well-controlled studies to validate the usefulness of plasma p-tau181 as an urgently needed surrogate marker for the diagnosis and disease progression of AD.

GENETIC DISSECTION OF SEVERITY AND ONSET MODULATORS FOR ALZHEIMER’S PATHOLOGY IN DOWN SYNDROME USING CELLULAR SYSTEMS

Trisomy of APP is responsible for extremely high incidence and early onset of AD pathology in Down syndrome (DS) brains. However, other genes on human chr21 likely modulate the age of onset, severity and modality of the clinical picture, as DS individuals have later or absent onset of clinical AD, and less intracerebral haemorrhage pathology, than euploid individuals with the familial early onset AD caused by a duplication of APP gene (dupAPP). Our aim is to identify such modulator genes on chr21 using cellular models. Neurons derived from isogenic hiPSCs we generated from a mosaic DS individual, unpublished iPSCs from segmental trisomy 21 DS and non-DS individuals, as well as from DS individuals with extremely early or late dementia onset are used in 2D, 3D and cerebral organoid paradigms. Optogenetic stimulation of Channelrhodopsin-2 engineered hiPSCs is used to determine the neuronal activity-dependent cellular phenotype modulation. CRISPR/Cas9 mediated reduction from trisomy to disomy for individual selected candidate genes on chr21 are performed on isogenic T21 iPSCs. We detect T21-caused neurodevelopmental delay, increased β-amyloid and phospho-Tau presence, complex mitochondrial dysfunction, accelerated DNA damage and abnormal endosomes, and some of these phenotypes exacerbate in 3D and cerebral organoid paradigms, and/or can be reproduced in primary human neuroectodermal cells expanded and differentiated in vitro. Cellular phenotypes relevant for AD pathology caused by trisomy21 can be reproduced and quantitatively assessed in iPSC-derived and primary NSC-derived neurons and differences sharpened by the use of cerebral organoid technology. Isogenic iPSCs allow detection of subtle changes in phenotypes and evaluation of single gene's trisomy contribution using CRISPR/Cas9 editing. Segmental trisomy 21 iPSCs allow for assignment of phenotype effects to a region of chromosome 21, and can faster eliminate some candidate genes.

ALZHEIMER’S DISEASE IN DOWN SYNDROME CAN BE PREVENTED BY PHARMACOLOGIC TREATMENT DURING PRENATAL TO EARLY POSTNATAL DEVELOPMENT

Alzheimer's disease (AD) is a multifactorial disorder. Down syndrome (DS) which is caused by trisomy 21, is one of the etiopathogenic mechanisms of AD. By the age 40, almost all DS individuals develop the histopathological characteristics of AD, and ∼70% of them develop dementia by age 60. The Ts65Dn trisomic mouse model of DS exhibits several key features of the disease including developmental delay and AD-like cognitive impairment and synaptic loss. Prenatal genetic testing to diagnose DS in utero, provides the novel opportunity to initiate early pharmacological treatment to target this critical period of brain development. We treated Ts65Dn mice from embryonic day 8 (E8) to weaning/postnatal day 21 with a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic, the compound P021 (200 nmoles/g diet administered to mothers/dams) and studied developmental milestones and during adult life cognitive performance. We found that Peptide 021 (P021), rescued developmental delay in pups and AD-like hippocampus-dependent memory impairments in adult life (5–7 months of age) in Ts65Dn mice. Furthermore, this treatment prevented synaptic loss and increased levels of synaptic plasticity markers including brain derived neurotrophic factor (BNDF) and phosphorylated CREB, both in young (3-week-old) and adult (∼ 7-monthold) Ts65Dn mice. These findings provide novel evidence that providing neurotrophic support during early brain development can prevent developmental delay and AD-like memory impairments and that AD can be a developmental defect with a late life onset.