Early neurotrophic pharmacotherapy rescues developmental delay and Alzheimer’s-like memory deficits in the Ts65Dn mouse model of Down syndrome

Kazim, Syed Faraz; Blanchard, Julie; Bianchi, R. M.; Iqbal, Khalid

doi:10.1038/srep45561

Cited by 26 publications

(24 citation statements)

References 158 publications

(289 reference statements)

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“…Moreover, the effect of DHF appeared to be consistent with previous studies showing that the administration of Neurotropin ® (a drug previously proposed as analgesic for chronic pain) or ciliary neurotrophic factor (CNTF) peptide to increase hippocampal BDNF expression in Ts65Dn mice is associated improved spatial memory 134 , 137 . Regarding translational opportunities afforded by the present results, physical exercise may represent a valuable complementary therapy aimed at rescuing cognitive disabilities in patients with DS.…”

Section: Discussionsupporting

confidence: 87%

“…However, BDNF expression was reduced in CA1 hippocampal neurons of elderly Ts65Dn mice 133 , indicating an age-related impairment in BDNF expression in trisomic mice. In this regard, some conflicting results have been reported in the literature, since BDNF expression was reduced in the hippocampus of both young and middle-aged Ts65Dn mice 134 – 137 . As BDNF expression is influenced by previous experience, gender, circadian rhythms or housing conditions 138 – 142 , differences in these variables and the analysis method used may explain the reported discrepancies.…”

Section: Discussionmentioning

confidence: 98%

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Aerobic exercise and a BDNF-mimetic therapy rescue learning and memory in a mouse model of Down syndrome

Parrini

Ghezzi

Deidda

et al. 2017

Sci Rep

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Down syndrome (DS) is caused by the triplication of human chromosome 21 and represents the most frequent genetic cause of intellectual disability. The trisomic Ts65Dn mouse model of DS shows synaptic deficits and reproduces the essential cognitive disabilities of the human syndrome. Aerobic exercise improved various neurophysiological dysfunctions in Ts65Dn mice, including hippocampal synaptic deficits, by promoting synaptogenesis and neurotransmission at glutamatergic terminals. Most importantly, the same intervention also prompted the recovery of hippocampal adult neurogenesis and synaptic plasticity and restored cognitive performance in trisomic mice. Additionally, the expression of brain-derived neurotrophic factor (BDNF) was markedly decreased in the hippocampus of patients with DS. Since the positive effect of exercise was paralleled by increased BDNF expression in trisomic mice, we investigated the effectiveness of a BDNF-mimetic treatment with 7,8-dihydroxyflavone at alleviating intellectual disabilities in the DS model. Pharmacological stimulation of BDNF signaling rescued synaptic plasticity and memory deficits in Ts65Dn mice. Based on our findings, Ts65Dn mice benefit from interventions aimed at promoting brain plasticity, and we provide evidence that BDNF signaling represents a potentially new pharmacological target for treatments aimed at rescuing cognitive disabilities in patients with DS.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 98%

Aerobic exercise and a BDNF-mimetic therapy rescue learning and memory in a mouse model of Down syndrome

Parrini

Ghezzi

Deidda

et al. 2017

Sci Rep

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“…We conducted the MWM test at 17 mo of age in study mice to assess hippocampus-dependent spatial reference learning and memory. The experimental paradigm used was an adaptation of the protocol originally described by Morris et al (94) in rats, and previously validated in mice (95)(96)(97). The MWM behavior task depends on the utilization of a spatial navigational strategy by rodents to find a fixed submerged escape platform.…”

Section: Methodsmentioning

confidence: 99%

Divergent roles of astrocytic versus neuronal EAAT2 deficiency on cognition and overlap with aging and Alzheimer’s molecular signatures

Sharma

Kazim

Larson

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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The excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter in the brain expressed predominantly in astrocytes and at low levels in neurons and axonal terminals. EAAT2 expression is reduced in aging and sporadic Alzheimer’s disease (AD) patients’ brains. The role EAAT2 plays in cognitive aging and its associated mechanisms remains largely unknown. Here, we show that conditional deletion of astrocytic and neuronal EAAT2 results in age-related cognitive deficits. Astrocytic, but not neuronal EAAT2, deletion leads to early deficits in short-term memory and in spatial reference learning and long-term memory. Neuronal EAAT2 loss results in late-onset spatial reference long-term memory deficit. Neuronal EAAT2 deletion leads to dysregulation of the kynurenine pathway, and astrocytic EAAT2 deficiency results in dysfunction of innate and adaptive immune pathways, which correlate with cognitive decline. Astrocytic EAAT2 deficiency also shows transcriptomic overlaps with human aging and AD. Overall, the present study shows that in addition to the widely recognized astrocytic EAAT2, neuronal EAAT2 plays a role in hippocampus-dependent memory. Furthermore, the gene expression profiles associated with astrocytic and neuronal EAAT2 deletion are substantially different, with the former associated with inflammation and synaptic function similar to changes observed in human AD and gene expression changes associated with inflammation similar to the aging human brain.

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“…A number of papers have described delays in achieving developmental milestones in DS murine models with respect to their euploid littermates (Aziz et al, 2018;Holtzman et al, 1996;Kazim, Blanchard, Bianchi, & Iqbal, 2017; also see Fig. 1).…”

Section: Critical Parametersmentioning

confidence: 99%

Behavioral Phenotyping for Down Syndrome in Mice

et al. 2020

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Down syndrome (DS) is the most frequent genetic cause of intellectual disability, characterized by alterations in different behavioral symptom domains: neurodevelopment, motor behavior, and cognition. As mouse models have the potential to generate data regarding the neurological basis for the specific behavioral profile of DS, and may indicate pharmacological treatments with the potential to affect their behavioral phenotype, it is important to be able to assess disease‐relevant behavioral traits in animal models in order to provide biological plausibility to the potential findings. The field is at a juncture that requires assessments that may effectively translate the findings acquired in mouse models to humans with DS. In this article, behavioral tests are described that are relevant to the domains affected in DS. A neurodevelopmental behavioral screen, the balance beam test, and the Multivariate Concentric Square Field test to assess multiple behavioral phenotypes and locomotion are described, discussing the ways to merge these findings to more fully understand cognitive strengths and weaknesses in this population. New directions for approaches to cognitive assessment in mice and humans are discussed. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Preweaning neurodevelopmental battery Basic Protocol 2: Balance beam Basic Protocol 3: Multivariate concentric square field test (MCSF)

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Early neurotrophic pharmacotherapy rescues developmental delay and Alzheimer’s-like memory deficits in the Ts65Dn mouse model of Down syndrome

Cited by 26 publications

References 158 publications

Aerobic exercise and a BDNF-mimetic therapy rescue learning and memory in a mouse model of Down syndrome

Aerobic exercise and a BDNF-mimetic therapy rescue learning and memory in a mouse model of Down syndrome

Divergent roles of astrocytic versus neuronal EAAT2 deficiency on cognition and overlap with aging and Alzheimer’s molecular signatures

Behavioral Phenotyping for Down Syndrome in Mice

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