Down syndrome

Rafii, Michael S.; Kleschevnikov, Alexander M.; Sawa, Mariko; Mobley, William C.

doi:10.1016/b978-0-12-804766-8.00017-0

Cited by 40 publications

(31 citation statements)

References 172 publications

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“…As above, proteins were extracted from the frontal cortex of AD-DS and controls for AD-DS (C/AD-DS) and KIF5 family members, and fl-hAPP levels were evaluated by Western blotting (Table 2). Consistent with the fact that the majority of adults with DS show the increased expression of the APP gene with increases in the levels of fl-APP [18,19,21], and as previously reported [55,56], we detected a significant increase in fl-hAPP normalized to β-actin in AD-DS brains relative to that in C/AD-DS (Fig. 3a, b).…”

Section: Kif5 Levels Were Not Changed In the Ad-ds Brainsupporting

confidence: 91%

Normal levels of KIF5 but reduced KLC1 levels in both Alzheimer disease and Alzheimer disease in Down syndrome: evidence suggesting defects in anterograde transport

et al. 2021

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Background Impaired axonal transport may contribute to the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD) and Down syndrome (DS). Axonal transport is a complex process in which specific motor proteins move cargoes to and from neuronal cell bodies and their processes. Inconsistent reports point to the changes in AD in the levels of the classical anterograde motor protein kinesin family member 5 (KIF5) and the primary neuronal KIF regulator kinesin light chain 1 (KLC1), raising the possibility that anterograde transport is compromised in AD. Methods and materials To address inconsistencies and determine if the shared pathologies in AD and elderly DS subjects with dementia (AD in DS; AD-DS) extend to the changes in KIF5 and KLC1, we measured the levels of all the three KIF5 family members and KLC1 in the AD and AD-DS frontal cortex and AD temporal cortex and cerebellum in samples taken with a short postmortem interval. To support future studies to explore the cell biological basis for any changes detected, we also examined the levels of these proteins in the brains of young and aged adult mice in the Dp (16)1Yey/+ (Dp16) mouse model of DS and J20 mouse model of AD. Results There were no changes in comparison with controls in KIF5 family members in either the AD or AD-DS samples when normalized to either β-actin or glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Interestingly, however, samples from control brains as well as from AD and AD-DS demonstrated strong positive correlations between the levels of KIF5 family members, suggesting positive co-regulated expression. Importantly, while earlier reports pointed to a negative correlation between the levels of the amyloid precursor protein (APP) and KIF5A levels, we found the opposite to be true in AD-DS; this was especially striking given triplication of the APP gene, with increased APP protein levels. AD and control samples showed positive correlations between fl-hAPP and KIF5 members, but they were less consistent. In contrast to the findings for KIF5, the levels of KLC1 were downregulated in the frontal cortex of both AD and AD-DS brains; interestingly, this change was not seen in the AD temporal cortex or cerebellum. As postmortem interval has a negative effect on the levels of KLC1, but not KIF5 members, we analyzed a subset of samples with a very short postmortem interval (PMI) (≤ 6 h), a PMI that was not significantly correlated with the levels of KLC1 in either AD or AD-DS samples; we confirmed the presence of a statistically significant reduction of KLC1 in AD and AD-DS brains as compared with control brains. Studies comparing Dp16 to its euploid control recapitulated human studies in demonstrating no change in KIF5 levels and a positive correlation between the levels of KIF5 family members. J20 mice also showed normal KIF5 levels. However, unlike the AD and AD-DS frontal cortex, KLC1 levels were not reduced in the brains of Dp16 or J20 mice. Conclusion These data point to significant reductions in KLC1 in AD and AD-DS. In so doing, they raise the possibility of compromised KLC1-mediated axonal transport in these conditions, a posit that can now be pursued in model systems in which KLC1 expression is reduced.

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Section: Kif5 Levels Were Not Changed In the Ad-ds Brainsupporting

confidence: 91%

Normal levels of KIF5 but reduced KLC1 levels in both Alzheimer disease and Alzheimer disease in Down syndrome: evidence suggesting defects in anterograde transport

et al. 2021

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“…10,23 Thus although children, adolescents, and young adults experience a common, albeit variable, set of clinical and cognitive challenges, 24 in a large fraction of the aging DS population a dementia syndrome ensues that shows many similarities to AD. 23,25,26 Beyond age 40, increasing deficits in recall, explicit memory, and receptive language function are the precursors of dementia. Dementia in DS is often marked by changes in behavior and personality, and by executive dysfunction.…”

Section: Historical Evolution and Current Perspectivementioning

confidence: 99%

“…Although studies of genetic risk variants for AD in DS has received little attention, the APOE ɛ4 allele is associated with increased accumulation of Aβ 28 and increased risk of earlier onset of dementia 29 . In summary, the remarkable correspondence between the general and DS populations in clinical manifestations, biomarkers, 30–33 and neuropathological features 34–36 justifies the designation of AD in DS (AD‐DS) 23 . It is notable that the necessary role played by increased APP gene dose in AD‐DS motivates, and may simplify, approaches for exploring AD pathogenesis and treatment of AD‐DS.…”

Section: Introductionmentioning

confidence: 99%

Targeting increased levels of APP in Down syndrome: Posiphen‐mediated reductions in APP and its products reverse endosomal phenotypes in the Ts65Dn mouse model

Chen

Salehi

Pearn

et al. 2020

Alzheimer's & Dementia

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Objective Recent clinical trials targeting amyloid beta (Aβ) and tau in Alzheimer's disease (AD) have yet to demonstrate efficacy. Reviewing the hypotheses for AD pathogenesis and defining possible links between them may enhance insights into both upstream initiating events and downstream mechanisms, thereby promoting discovery of novel treatments. Evidence that in Down syndrome (DS), a population markedly predisposed to develop early onset AD, increased APP gene dose is necessary for both AD neuropathology and dementia points to normalization of the levels of the amyloid precursor protein (APP) and its products as a route to further define AD pathogenesis and discovering novel treatments. Background AD and DS share several characteristic manifestations. DS is caused by trisomy of whole or part of chromosome 21; this chromosome contains about 233 protein‐coding genes, including APP. Recent evidence points to a defining role for increased expression of the gene for APP and for its 99 amino acid C‐terminal fragment (C99, also known as β‐CTF) in dysregulating the endosomal/lysosomal system. The latter is critical for normal cellular function and in neurons for transmitting neurotrophic signals. New/updated hypothesis We hypothesize that the increase in APP gene dose in DS initiates a process in which increased levels of full‐length APP (fl‐APP) and its products, including β‐CTF and possibly Aβ peptides (Aβ42 and Aβ40), drive AD pathogenesis through an endosome‐dependent mechanism(s), which compromises transport of neurotrophic signals. To test this hypothesis, we carried out studies in the Ts65Dn mouse model of DS and examined the effects of Posiphen, an orally available small molecule shown in prior studies to reduce fl‐APP. In vitro, Posiphen lowered fl‐APP and its C‐terminal fragments, reversed Rab5 hyperactivation and early endosome enlargement, and restored retrograde transport of neurotrophin signaling. In vivo, Posiphen treatment (50 mg/kg/d, 26 days, intraperitoneal [i.p.]) of Ts65Dn mice was well tolerated and demonstrated no adverse effects in behavior. Treatment resulted in normalization of the levels of fl‐APP, C‐terminal fragments and small reductions in Aβ species, restoration to normal levels of Rab5 activity, reduced phosphorylated tau (p‐tau), and reversed deficits in TrkB (tropomyosin receptor kinase B) activation and in the Akt (protein kinase B [PKB]), ERK (extracellular signal‐regulated kinase), and CREB (cAMP response element–binding protein) signaling pathways. Remarkably, Posiphen treatment also restored the level of choline acetyltransferase protein to 2N levels. These findings support the APP gene dose hypothesis, point to the need for additional studies to explore the mechanisms by which increased APP gene expression acts to increase the risk for AD in DS, and to possible utility of treatments to normalize the levels of APP and its products for preventing AD in those with DS. Major challenges for the hypothesis Important unanswered questions are: (1) When should one intervene in t...

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“…These demands include treatment, both medically and traditional, as well as alternative therapies, because the condition features a variety of problems, especially health disorders. The immune system also tends to be very poor against disease, hence routine health checks are urgently required [22]. Meanwhile, meeting the needs of daily activities involves teaching basic habits, including eating, bathing and dressing, which is often conducted by the mother.…”

Section: Discussionmentioning

confidence: 99%

Experiences of mothers of children with Down syndrome

Suza¹,

Napitupulu²,

Hariati³

2020

fmpcr

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Background. Down syndrome is a genetically occurring chromosomal abnormality, characterized by mild to moderate intellectual impairment, difficulties in verbal and non-verbal communication, as well as disruption in social interactions. In addition, mothers of affected children possess various emotional experiences and must have strategies to provide optimal care in the face some physical and social challenges. Objectives. The aim of this study was to describe the experiences of mothers of children with Down syndrome. Material and methods. This was a qualitative research with a phenomenological approach, and the participants consisted of 10 mothers selected through purposive sampling. In addition, the study was conducted in Binjai, Indonesia, from April to May 2018. Data collection was performed using in-depth interviews with voice recording. Content analysis was adopted using the Collaizi method, and the principle of trustworthiness was subsequently applied. Results. A total of 5 themes were recognized, including 1) having an emotional experience, 2) accepting the child's situation, 3) meeting the needs of children, 4) experiencing obstacles in caring for children and 5) expectation of the mother. Conclusions. The study, based on the experiences of mothers of children with Down syndrome, provides important information for families, health workers and the health service system to enhance understanding of the condition, as well as the appropriate handling techniques. Furthermore, it is also necessary to further investigate the experiences of positive emotions in affected mothers.

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Down syndrome

Cited by 40 publications

References 172 publications

Normal levels of KIF5 but reduced KLC1 levels in both Alzheimer disease and Alzheimer disease in Down syndrome: evidence suggesting defects in anterograde transport

Normal levels of KIF5 but reduced KLC1 levels in both Alzheimer disease and Alzheimer disease in Down syndrome: evidence suggesting defects in anterograde transport

Targeting increased levels of APP in Down syndrome: Posiphen‐mediated reductions in APP and its products reverse endosomal phenotypes in the Ts65Dn mouse model

Experiences of mothers of children with Down syndrome

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