The use of mouse models to understand and improve cognitive deficits in Down syndrome

Abstract

Remarkable advances have been made in recent years towards therapeutics for cognitive impairment in individuals with Down syndrome (DS) by using mouse models. In this review, we briefly describe the phenotypes of mouse models that represent outcome targets for drug testing, the behavioral tests used to assess impairments in cognition and the known mechanisms of action of several drugs that are being used in preclinical studies or are likely to be tested in clinical trials. Overlaps in the distribution of targets and in the pathways that are affected by these diverse drugs in the trisomic brain suggest new avenues for DS research and drug development.

Longitudinal measures of cognition in the Ts65Dn mouse: Refining windows and defining modalities for therapeutic intervention in Down syndrome

“…The trisomic Ts65Dn mouse is currently the most commonly employed model of DS, mainly because it displays several phenotypic abnormalities which parallel those found in DS, including delays in brain development, hyperactivity, and motor dysfunction (Davisson et al, 1993; Costa et al, 1999; Chakrabarti et al, 2007; Sanders et al, 2009). In addition, several studies have reported cognitive impairment in Ts65Dn mice using a variety of behavioral paradigms, primarily examining spatial learning and memory (L/M) (Das and Reeves, 2011; Ruparelia et al, 2013). While these studies provide a framework of the L/M impairments in Ts65Dn, key questions about the onset and magnitude of these deficits as well as in-depth assessment over an extended period of time remain unanswered.…”

Comparative proteomic profiling reveals aberrant cell proliferation in the brain of embryonic Ts1Cje, a mouse model of Down syndrome

“…Several mouse models of DS have been used to investigate the pathomechanisms of DS symptoms in vivo (Das and Reeves, 2011;Edgin et al, 2012;Haydar and Reeves, 2012;Yamakawa, 2012). Because the distal end of mouse chromosome 16 (MMU16) is syntenic with the large part of HSA21, the mouse models of DS, such as the Ts65Dn, Ts1Cje, Tc1, Ts1Rhr and Ts1Yey strains carry full or segmental trisomy of MMU16 (Davisson et al, 1990;Sago et al, 1998;Olson et al, 2004;O'Doherty et al, 2005;Yu et al, 2010).…”

An investigation of the molecular mechanisms engaged before and after the development of Alzheimer disease neuropathology in Down syndrome: a proteomics approach

“…In addition to intellectual disability, virtually all DS brains over 40 years of age show Alzheimer disease (AD) neuropathology [3], including the presence of senile plaque (SP) and neurofibrillary tangles (NFT) [3–5], and clinical signs of dementia become more frequent after 50 years of age [6, 7]. Several studies support the hypothesis that the over-expression of genes present on chromosome 21 is responsible for the features of DS, including the development of AD [8, 9]. The over-expression of amyloid precursor protein (APP), due to its location on chromosome 21, leads to an enhanced production of beta-amyloid (Aβ), the principle component of SP.…”