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Review
. 2016;13(1):35-52.
doi: 10.2174/1567205012666150921095505.

Cognitive Impairment, Neuroimaging, and Alzheimer Neuropathology in Mouse Models of Down Syndrome

Eric D Hamlett, Heather A Boger, Aurélie Ledreux, Christy M Kelley, Elliott J Mufson, Maria F Falangola, David N Guilfoyle, Ralph A Nixon, David Patterson, Nathan Duval, Ann-Charlotte E Granholm  1
Affiliations
Review

Cognitive Impairment, Neuroimaging, and Alzheimer Neuropathology in Mouse Models of Down Syndrome

Eric D Hamlett et al. Curr Alzheimer Res. 2016.

Abstract

Down syndrome (DS) is the most common non-lethal genetic condition that affects approximately 1 in 700 births in the United States of America. DS is characterized by complete or segmental chromosome 21 trisomy, which leads to variable intellectual disabilities, progressive memory loss, and accelerated neurodegeneration with age. During the last three decades, people with DS have experienced a doubling of life expectancy due to progress in treatment of medical comorbidities, which has allowed this population to reach the age when they develop early onset Alzheimer's disease (AD). Individuals with DS develop cognitive and pathological hallmarks of AD in their fourth or fifth decade, and are currently lacking successful prevention or treatment options for dementia. The profound memory deficits associated with DS-related AD (DS-AD) have been associated with degeneration of several neuronal populations, but mechanisms of neurodegeneration are largely unexplored. The most successful animal model for DS is the Ts65Dn mouse, but several new models have also been developed. In the current review, we discuss recent findings and potential treatment options for the management of memory loss and AD neuropathology in DS mouse models. We also review agerelated neuropathology, and recent findings from neuroimaging studies. The validation of appropriate DS mouse models that mimic neurodegeneration and memory loss in humans with DS can be valuable in the study of novel preventative and treatment interventions, and may be helpful in pinpointing gene-gene interactions as well as specific gene segments involved in neurodegeneration.

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Conflict of interest statement

The author(s) confirm that this article content has no conflicts of interest.

Figures

Fig. 1
Fig. 1
Summary of available DS mouse models to date. Hsa = human chromosome, Mmu = murine chromosome, gray lines delineates included gene segments per mouse, and light gray dotted box represents the so called Down syndrome Critical Region (DSCR).
Fig. 2
Fig. 2
(A) = Analysis of WRAM performance in Ts65Dn mice (gray symbols) and age-matched NS mice (black symbols) from several different experiments across age. Note that the Ts65Dn mice exhibit no statistical difference in average errors the first 4 trials, indicating that they are capable of performing the task, but have significantly more average errors during the last 4 trials, indicating significant reduction in learning. (B) Analysis of total spontaneous activity (in cm) in Ts65Dn mice (gray) and age-matched normosomic mice (NS, black) across several different experiments. Note that there is significant hyperactivity at all ages examined (6–13 months of age). (C) Analysis of locus coeruleus (LC) phenotypic loss from 4 to 13 months of age. TS = Ts65Dn; NS = normosomic. Comparative study across several different cohorts of mice. There is a progressive loss of LC neurons with age, most notable at 13 months of age.
Fig 3
Fig 3
Cell loss in basal forebrain (TrkA staining), hippocampus (Calbindin), and locus coeruleus (tyrosine hydroxylase, TH) in middleaged Ts65Dn mice compared to age-matched normosomic mice (NS). In all these three neuronal populations, there is a progressive loss of phenotype with age, starting at 6 months of age. For BFCNs, this phenotypic loss is significant at 8 months of age, and for the LC and hippocampal neurons at 10–12 months of age. As can be seen in these representative images, phenotypic loss is accompanied by neurodegenerative shrinkage of cell bodies. Scale bar in (A) represents 150 microns, in (D) 60 microns, and in (F) 50 microns.
See this image and copyright information in PMC

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