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Rodent Modeling of Alzheimer's Disease in Down Syndrome: In vivo and ex vivo Approaches

Farrell, Cliona; Mumford, Paige; Wiseman, Frances K; (2022) Rodent Modeling of Alzheimer's Disease in Down Syndrome: In vivo and ex vivo Approaches. Frontiers in Neuroscience , 16 , Article 909669. 10.3389/fnins.2022.909669. Green open access

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Abstract

There are an estimated 6 million people with Down syndrome (DS) worldwide. In developed countries, the vast majority of these individuals will develop Alzheimer's disease neuropathology characterized by the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles within the brain, which leads to the early onset of dementia (AD-DS) and reduced life-expectancy. The mean age of onset of clinical dementia is ~55 years and by the age of 80, approaching 100% of individuals with DS will have a dementia diagnosis. DS is caused by trisomy of chromosome 21 (Hsa21) thus an additional copy of a gene(s) on the chromosome must cause the development of AD neuropathology and dementia. Indeed, triplication of the gene APP which encodes the amyloid precursor protein is sufficient and necessary for early onset AD (EOAD), both in people who have and do not have DS. However, triplication of other genes on Hsa21 leads to profound differences in neurodevelopment resulting in intellectual disability, elevated incidence of epilepsy and perturbations to the immune system. This different biology may impact on how AD neuropathology and dementia develops in people who have DS. Indeed, genes on Hsa21 other than APP when in three-copies can modulate AD-pathogenesis in mouse preclinical models. Understanding this biology better is critical to inform drug selection for AD prevention and therapy trials for people who have DS. Here we will review rodent preclinical models of AD-DS and how these can be used for both in vivo and ex vivo (cultured cells and organotypic slice cultures) studies to understand the mechanisms that contribute to the early development of AD in people who have DS and test the utility of treatments to prevent or delay the development of disease.

Type: Article
Title: Rodent Modeling of Alzheimer's Disease in Down Syndrome: In vivo and ex vivo Approaches
Location: Switzerland
Open access status: An open access version is available from UCL Discovery
DOI: 10.3389/fnins.2022.909669
Publisher version: https://doi.org/10.3389/fnins.2022.909669
Language: English
Additional information: Copyright © 2022 Farrell, Mumford and Wiseman. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Keywords: Science & Technology, Life Sciences & Biomedicine, Neurosciences, Neurosciences & Neurology, Down syndrome, Alzheimer's disease, Amyloid-beta, tau, mouse model, neuronal loss, neuroinflammation, AMYLOID PRECURSOR PROTEIN, NERVE GROWTH-FACTOR, APP LOCUS DUPLICATION, TS65DN MOUSE MODEL, LEWY BODY DISEASE, A-BETA, COGNITIVE DECLINE, ANIMAL-MODEL, MIDDLE-AGE, TAU HYPERPHOSPHORYLATION
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
URI: https://discovery.ucl.ac.uk/id/eprint/10151252
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