Pharmacotherapy of Down’s Syndrome: When and Which?

Tayebati, Seyed Khosrow; Cecchi, A; Martinelli, Ilenia; Carboni, Elisa; Amenta, Francesco

doi:10.2174/1871527318666191114092924

Cited by 5 publications

(4 citation statements)

References 76 publications

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“…Several pharmacotherapies have been reported to rescue the neuromorphological and cognitive deficits in murine models of DS (Malberg et al, 2000;Clark et al, 2006;Bianchi et al, 2010aBianchi et al, , 2010bContestabile et al, 2013;Martínez-Cué et al, 2013;Guidi et al, 2014;Stagni et al, 2015Stagni et al, , 2016Stagni et al, , 2017Stagni et al, , 2019Navarro-Romero et al, 2019;Zhou et al, 2019). However, some of these drugs did not demonstrate any clinical benefit when tested in humans, or cannot be safely administered to individuals with DS (Gardiner, 2014;Tayebati et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Bexarotene Impairs Cognition and Produces Hypothyroidism in a Mouse Model of Down Syndrome and Alzheimer’s Disease

et al. 2021

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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.

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Section: Introductionmentioning

confidence: 99%

Bexarotene Impairs Cognition and Produces Hypothyroidism in a Mouse Model of Down Syndrome and Alzheimer’s Disease

et al. 2021

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“…Cholinergic therapies have been advocated for DS to ameliorate dysfunctional neuronal circuitry ( Kishnani et al, 2001 ). The available AD-related pharmacologic therapies offer minimal usefulness in symptom reduction and fail to stop or slow down disease progression ( Areosa and Sherriff, 2003 ; Cacabelos, 2007 ; Folch et al, 2018 ; Tayebati et al, 2019 ). Yet, combined treatment with cholinesterase inhibitors and memantine have also been used to ameliorate both cognitive and behavioral issues in AD and DS.…”

Section: Interventions For Ad and Dsmentioning

confidence: 99%

Basal Forebrain Cholinergic Neurons: Linking Down Syndrome and Alzheimer’s Disease

Martínez

Zammit

West

et al. 2021

Front. Aging Neurosci.

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Down syndrome (DS, trisomy 21) is characterized by intellectual impairment at birth and Alzheimer’s disease (AD) pathology in middle age. As individuals with DS age, their cognitive functions decline as they develop AD pathology. The susceptibility to degeneration of a subset of neurons, known as basal forebrain cholinergic neurons (BFCNs), in DS and AD is a critical link between cognitive impairment and neurodegeneration in both disorders. BFCNs are the primary source of cholinergic innervation to the cerebral cortex and hippocampus, as well as the amygdala. They play a critical role in the processing of information related to cognitive function and are directly engaged in regulating circuits of attention and memory throughout the lifespan. Given the importance of BFCNs in attention and memory, it is not surprising that these neurons contribute to dysfunctional neuronal circuitry in DS and are vulnerable in adults with DS and AD, where their degeneration leads to memory loss and disturbance in language. BFCNs are thus a relevant cell target for therapeutics for both DS and AD but, despite some success, efforts in this area have waned. There are gaps in our knowledge of BFCN vulnerability that preclude our ability to effectively design interventions. Here, we review the role of BFCN function and degeneration in AD and DS and identify under-studied aspects of BFCN biology. The current gaps in BFCN relevant imaging studies, therapeutics, and human models limit our insight into the mechanistic vulnerability of BFCNs in individuals with DS and AD.

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“…Mouse genetic models have been successfully used to examine structural and functional abnormalities of DS in invasive experiments ( Dierssen et al, 2001 ; Belichenko et al, 2004 ; Salehi et al, 2006 ; Yu et al, 2010 ; Gotti et al, 2011 ; Liu et al, 2011 ; Popov et al, 2011 ; Kleschevnikov et al, 2012c ; Cramer and Galdzicki, 2012 ; Haydar and Reeves, 2012 ; Ruparelia et al, 2012 ; Zhang et al, 2012 ; Zhang et al, 2014 ; Belichenko et al, 2015 ). In addition, genetic models of DS have been instrumental for the discovery and evaluation of potential treatments to improve the impaired cognition ( Dierssen et al, 2001 ; Belichenko et al, 2007 ; Dierssen et al, 2009 ; Salehi et al, 2009 ; Faizi et al, 2011 ; Kleschevnikov et al, 2012a ; Kleschevnikov et al, 2012c ; Haydar and Reeves, 2012 ; Lott, 2012 ; Mohler, 2012 ; Rueda et al, 2012 ; Ruparelia et al, 2012 ; Lysenko et al, 2014 ; Martinez-Cue et al, 2014 ; Belichenko et al, 2016 ; Hamlett et al, 2016 ; Reeves et al, 2019 ; Tayebati et al, 2019 ; Chen et al, 2020 ). The most extensively used genetic model of DS, Ts65Dn mice, are segmentally trisomic for the mouse chromosome 16 region that is syntenic to a subregion of HSA21 containing DSCR.…”

Section: Girk2 Channels In Down Syndrome Modelsmentioning

confidence: 99%

“…GIRK2 channels in Down syndrome models Zhang et al, 2012;Zhang et al, 2014;Belichenko et al, 2015). In addition, genetic models of DS have been instrumental for the discovery and evaluation of potential treatments to improve the impaired cognition (Dierssen et al, 2001;Belichenko et al, 2007;Dierssen et al, 2009;Salehi et al, 2009;Faizi et al, 2011;Kleschevnikov et al, 2012a;Kleschevnikov et al, 2012c;Haydar and Reeves, 2012;Lott, 2012;Mohler, 2012;Rueda et al, 2012;Ruparelia et al, 2012;Lysenko et al, 2014;Martinez-Cue et al, 2014;Belichenko et al, 2016;Hamlett et al, 2016;Reeves et al, 2019;Tayebati et al, 2019;Chen et al, 2020). The most extensively used genetic model of DS, Ts65Dn mice, are segmentally trisomic for the mouse chromosome 16 region that is syntenic to a subregion of HSA21 containing DSCR.…”

Section: Properties Of Girk2 Channelsmentioning

confidence: 99%

Enhanced GIRK2 channel signaling in Down syndrome: A feasible role in the development of abnormal nascent neural circuits

Kleschevnikov

2022

Front. Genet.

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The most distinctive feature of Down syndrome (DS) is moderate to severe cognitive impairment. Genetic, molecular, and neuronal mechanisms of this complex DS phenotype are currently under intensive investigation. It is becoming increasingly clear that the abnormalities arise from a combination of initial changes caused by triplication of genes on human chromosome 21 (HSA21) and later compensatory adaptations affecting multiple brain systems. Consequently, relatively mild initial cognitive deficits become pronounced with age. This pattern of changes suggests that one approach to improving cognitive function in DS is to target the earliest critical changes, the prevention of which can change the ‘trajectory’ of the brain development and reduce the destructive effects of the secondary alterations. Here, we review the experimental data on the role of KCNJ6 in DS-specific brain abnormalities, focusing on a putative role of this gene in the development of abnormal neural circuits in the hippocampus of genetic mouse models of DS. It is suggested that the prevention of these early abnormalities with pharmacological or genetic means can ameliorate cognitive impairment in DS.

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Pharmacotherapy of Down’s Syndrome: When and Which?

Cited by 5 publications

References 76 publications

Bexarotene Impairs Cognition and Produces Hypothyroidism in a Mouse Model of Down Syndrome and Alzheimer’s Disease

Bexarotene Impairs Cognition and Produces Hypothyroidism in a Mouse Model of Down Syndrome and Alzheimer’s Disease

Basal Forebrain Cholinergic Neurons: Linking Down Syndrome and Alzheimer’s Disease

Enhanced GIRK2 channel signaling in Down syndrome: A feasible role in the development of abnormal nascent neural circuits

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