Abstract
All individuals with Down syndrome (DS) eventually develop Alzheimer’s disease (AD) neuropathology, including neurodegeneration, increases in β-amyloid (Aβ) expression, and aggregation and neurofibrillary tangles, between the third and fourth decade of their lives. There is currently no effective treatment to prevent AD neuropathology and the associated cognitive degeneration in DS patients. Due to evidence that the accumulation of Aβ aggregates in the brain produces the neurodegenerative cascade characteristic of AD, many strategies which promote the clearance of Aβ peptides have been assessed as potential therapeutics for this disease. Bexarotene, a member of a subclass of retinoids that selectively activates retinoid receptors, modulates several pathways essential for cognitive performance and Aβ clearance. Consequently, bexarotene might be a good candidate to treat AD-associated neuropathology. However, the effects of bexarotene treatment in AD remain controversial. In the present study, we aimed to elucidate whether chronic bexarotene treatment administered to the most commonly used murine model of DS, the Ts65Dn (TS) mouse could reduce Aβ expression in their brains and improve their cognitive abilities. Chronic administration of bexarotene to aged TS mice and their CO littermates for 9 weeks diminished the reference, working, and spatial learning and memory of TS mice, and the spatial memory of CO mice in the Morris water maze. This treatment also produced marked hypoactivity in the plus maze, open field, and hole board tests in TS mice, and in the open field and hole board tests in CO mice. Administration of bexarotene reduced the expression of Aβ1-40, but not of Aβ1-42, in the hippocampi of TS mice. Finally, bexarotene increased Thyroid-stimulating hormone levels in TS mice and reduced Thyroid-stimulating hormone levels in CO mice, while animals of both karyotypes displayed reduced thyroxine levels after bexarotene administration. The bexarotene-induced hypothyroidism could be responsible for the hypoactivity of TS and CO mice and their diminished performance in the Morris water maze. Together, these results do not provide support for the use of bexarotene as a potential treatment of AD neuropathology in the DS population.
Highlights
Down syndrome (DS), the most common genetic cause of intellectual disability, is caused by a partial or complete triplication of the human chromosome 21 (Antonarakis et al, 2020)
Because DS is a useful model for investigating sporadic Alzheimer’s disease (AD) and potential pharmacotherapies to treat this disorder, we aimed to evaluate the effects of chronic bexarotene administration to aged TS mice, which display many hallmarks of AD, on their cognitive and behavioral abilities and their brain Aβ loads
Morris Water Maze Reference Memory During the 12 acquisition sessions, all mice reduced their latency to reach the platform across sessions (RM Analysis of Variance (ANOVA) ‘session’: p < 0.001)
Summary
Down syndrome (DS), the most common genetic cause of intellectual disability, is caused by a partial or complete triplication of the human chromosome 21 (Antonarakis et al, 2020). The cognitive alterations found in DS are primarily caused by prenatal changes in central nervous system growth and differentiation (Contestabile et al, 2007; Guidi et al, 2008; Haydar and Reeves, 2012; Lott, 2012; Rueda et al, 2012; Hibaoui et al, 2014; Stagni et al, 2018). These alterations are aggravated in later life stages. The knowledge obtained in animal models of DS will help to foster a better understanding of the causes of neurodegeneration and dementia, both in DS and in sporadic AD, and assist in the development of new therapeutic strategies to treat them
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