Insights from mouse models to understand neurodegeneration in Down syndrome.
Individuals with trisomy 21, also known as Down syndrome (DS), develop a clinical syndrome including almost identical neuropathological characteristics of Alzheimer's disease (AD) observed in non-DS individuals. The main difference is the early age of onset of AD pathology in individuals with DS, with hish incidence of clinical symptoms in the late 40- early 50 years of age. The neuropathology of AD in persons with DS is superimposed with the developmental abnormalities causing alterations of neuronal morphology and function. Despite the ubiquitous occurrence of AD neuropathology, clinical signs of dementia do not occur in all adults with DS even at older ages. Phenotype analysis of DS mouse models has revealed a differential age-related neurodegenerative pattern that correlates with specific biochemical and molecular alterations at the cellular level. In fact, several individual genes found in trisomy in DS have been functionally related to neuronal degeneration. Thus, mouse models overexpressing HSA21 gene(s) are fundamental to understand the neurodegenerative process in DS, as described in the present review. In addition, these models might allow to define and evaluate potential drug targets and to develop therapeutic strategies that may interfere or delay the onset of AD.
Fillat
Cristina
C
Centre de Regulació Genòmica, UPF, Parc de Recerca Biomèdica de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Raras, Spain. cristina.fillat@crg.es
Dierssen
Mara
M
de Lagrán
María Martínez
MM
Altafaj
Xavier
X
D000328:Adult; D000544:Alzheimer Disease / Q000473:pathology; D000818:Animals; D001921:Brain / Q000473:pathology; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics / Q000473:pathology*; D005796:Genes / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic / Q000254:growth & development; D008875:Middle Aged; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000473:pathology*