Alzheimer's disease in Down syndrome: Neurobiology and risk

Zigman, Warren B.; Lott, Ira T.

doi:10.1002/mrdd.20163

Cited by 249 publications

(242 citation statements)

References 157 publications

(153 reference statements)

Supporting

Mentioning

226

Contrasting

Unclassified

Order By: Relevance

“…Therefore, a unique mechanism may be in play in Ts21 cells during early developmental stages, where compensatory changes in OS genes allow for nearly normal cell proliferation and differentiation but cells remain highly susceptible to insults later in development (38,(47)(48)(49)(50). This mechanism may exacerbate the consequences of APP overexpression that predispose DS individuals to develop Alzheimer's disease pathology (51)(52)(53)(54).…”

Section: Discussionmentioning

confidence: 99%

Deficits in human trisomy 21 iPSCs and neurons

Weick

Held

Bonadurer

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

178

214

View full text Add to dashboard Cite

Down syndrome (trisomy 21) is the most common genetic cause of intellectual disability, but the precise molecular mechanisms underlying impaired cognition remain unclear. Elucidation of these mechanisms has been hindered by the lack of a model system that contains full trisomy of chromosome 21 (Ts21) in a human genome that enables normal gene regulation. To overcome this limitation, we created Ts21-induced pluripotent stem cells (iPSCs) from two sets of Ts21 human fibroblasts. One of the fibroblast lines had low level mosaicism for Ts21 and yielded Ts21 iPSCs and an isogenic control that is disomic for human chromosome 21 (HSA21). Differentiation of all Ts21 iPSCs yielded similar numbers of neurons expressing markers characteristic of dorsal forebrain neurons that were functionally similar to controls. Expression profiling of Ts21 iPSCs and their neuronal derivatives revealed changes in HSA21 genes consistent with the presence of 50% more genetic material as well as changes in non-HSA21 genes that suggested compensatory responses to oxidative stress. Ts21 neurons displayed reduced synaptic activity, affecting excitatory and inhibitory synapses equally. Thus, Ts21 iPSCs and neurons display unique developmental defects that are consistent with cognitive deficits in individuals with Down syndrome and may enable discovery of the underlying causes of and treatments for this disorder.cerebral cortex | developmental disorders D own syndrome (DS) is the most frequent single cause of human birth defects and intellectual disability (ID) (1). DS is caused by trisomy of chromosome 21 (Ts21) (2), resulting in the triplication of over 400 genes (3-5), which makes elucidation of the precise mechanisms underlying ID in DS a significant challenge. Confounding this difficulty is the relative inaccessibility of human tissue and incomplete human Ts21 in the context of mouse models. Despite these shortcomings, studies using mouse models containing trisomy of parts of syntenic chromosome 21 (HSA21) have put forth several critical hypotheses on the cellular and molecular mechanisms underlying DS features. It is essential, however, to test these hypotheses in human cells with full triplication of HSA21 in a context that allows for normal gene regulation. Here, we used Ts21-induced pluripotent stem cells (iPSCs) to test hypotheses of the underlying causes of ID in DS, with specific regard to neuropathophysiology. ResultsIsogenic Human Ts21 iPSCs. Fibroblasts from two individuals diagnosed with DS were reprogrammed to iPSCs. FISH for HSA21 in one fibroblast line showed mosaicism, where ∼90% of cells carried Ts21, whereas ∼10% were euploid (Fig. 1A). Reprogramming of the mosaic fibroblasts by retrovirus (6) resulted in three viable iPSC clones, two clones that carried Ts21 and one euploid (Fig. 1B). Mosaicism in DS individuals is rare, occurring in ∼1-3% of DS cases (7), but it can also emerge in vitro (8), potentially because of nondisjunction events during cell division.

show abstract

Section: Discussionmentioning

confidence: 99%

Deficits in human trisomy 21 iPSCs and neurons

Weick

Held

Bonadurer

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

178

214

View full text Add to dashboard Cite

show abstract

“…• Variables asociadas con mayor riesgo de sufrir EA en personas con SD El riesgo de padecer EA puede deberse a muchos factores y, aunque éste es alto en las personas con SD, la demencia no siempre aparece de forma inevitable, ni siquiera en edades avanzadas (Zigman y Lott, 2007). La mayoría de las personas con SD empiezan a desarrollar síntomas neuropatológicos de la EA a la edad de 30 años (Holland, 1995).…”

Section: Resultsunclassified

“…Algunos autores (Hoshino et al, 2002;Isbir et al, 2001) sugieren que existe una relación entre el colesterol, el APOE y el riesgo de padecer EA, probablemente debido al hecho de que el colesterol es transportado por lipoproteínas de alta densidad como el APOE (Launer et al, 2001). Los datos siguen apoyando el papel del amiloide y el estrés oxidativo en la neurobiología del Alzheimer y la importancia de contar con biomarcadores sensibles y específicos de la progresión clínica y patológica de esta enfermedad en adultos con SD (Zigman y Lott, 2007). Jones et al (2013) exponen que aún no se han estudiado ampliamente los factores de riesgo genéticos asociados a la temprana aparición de este tipo de demencia.…”

Section: Resultsunclassified

“…La proteína ßA está formada por péptidos creados a partir de la proteína precursora de amiloide (APP), cuyo gen se encuentra en el cromosoma 21, de ahí su interés en el SD (Parajuá-Pozo y Casis-Arguea, 2000). Además, el fenotipo de la alipoproteína E (APOE) está asociado con un alto riesgo de EA y un inicio temprano de demencia, tanto en las personas con SD como en población general (Zigman y Lott, 2007). No obstante, la presencia de estas lesiones neuropatológicas no conlleva necesariamente que la demencia aparezca de forma inevitable, ni siquiera en edades avanzadas, ya que el riesgo de padecer EA puede deberse a muchos factores (Jones et al, 2013;Zigman y Lott, 2007).…”

Section: Introductionunclassified

See 1 more Smart Citation

Síndrome de Down y enfermedad de Alzheimer: factores de riesgo, evaluación e intervención

Pérez

Gómez

Rodríguez

2016

Redis

View full text Add to dashboard Cite

Existe una estrecha relación entre el síndrome de Down y la enfermedad de Alzheimer. Diversos factores de riesgo influyen en esta relación, en la que la evaluación de la demencia es difícil debido a la falta de instrumentos y tratamientos específicos. Se realizó una búsqueda de los años comprendidos entre 2005-2015 en diferentes bases de datos. Se identificaron diversos factores de riesgo (genéticos, ambientales, cognitivos) y se encontraron varios instrumentos de evaluación, poco adecuados y/o con debilidades psicométricas. Los tratamientos existentes son escasos y, casi exclusivamente, farmacológicos. Se discute acerca de la importancia de llevar a cabo estudios sistemáticos sobre los factores de riesgo para la prevención de la enfermedad de Alzheimer en personas con síndrome de Down, así como la necesidad de un protocolo de evaluación específico y adaptado que permita implementar tratamientos más específicos y efectivos.

show abstract

“…While Alzheimer's disease was once considered an inexorable result of growing old with Down syndrome, recent data indicate that risk does not reach 100%. Although some individuals exhibit signs and symptoms of Alzheimer's disease in their 40s, other individuals have reached the age of 70 without dementia (Head, Lott, Patterson, Doran, & Haier, 2007;Schupf, 2002;Zigman & Lott, 2007), and it is important to understand the mechanisms responsible for these substantial individual differences if promotion of successful aging is to be maximized.…”

Section: Chapter Organizationmentioning

confidence: 99%