Reduction in neuronal L-type calcium channel activity in a double knock-in mouse model of Alzheimer's disease

Thibault, Olivier; Pancani, Tristano; Landfield, Philip W.; Norris, Christopher M.

doi:10.1016/j.bbadis.2012.01.004

Cited by 38 publications

(34 citation statements)

References 43 publications

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“…Such results are generally similar to those described above for studies of normal aging in hippocampal neurons, in that Ca 2+ dyshomeostasis was in part manifested by altered CICR. On the other hand, in contrast to normal aging, hippocampal L-VGCC activity was recently found to be reduced in a transgenic AD model compared to wild-type controls, possibly because of Ca 2+ inactivation (Thibault et al, 2012). …”

Section: Neuronal Calcium (Ca2+) Dysregulation With Agingmentioning

confidence: 99%

FK506-binding protein 1b/12.6: A key to aging-related hippocampal Ca2+ dysregulation?

Gant

Blalock

Chen

et al. 2014

European Journal of Pharmacology

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It has been recognized for some time that the Ca2+-dependent slow afterhyperpolarization (sAHP) is larger in hippocampal neurons of aged compared with young animals. In addition, extensive studies since have shown that other Ca2+-mediated electrophysiological responses are increased in hippocampus with aging, including Ca2+ transients, L-type voltage-gated Ca2+ channel activity, Ca2+ spike duration and action potential accommodation. Elevated Ca2+-induced Ca2+ release from ryanodine receptors (RyRs) appears to drive amplification of the Ca2+ responses. Components of this Ca2+ dysregulation phenotype correlate with deficits in cognitive function and plasticity, indicating they may play critical roles in aging-related impairment of brain function. However, the molecular mechanisms underlying aging-related Ca2+ dysregulation are not well understood. FK506-binding proteins 1a and 1b (FKBP1a/1b, also known as FKBP12/12.6) are immunophilin proteins that bind the immunosuppressant drugs FK506 and rapamycin. In muscle cells, FKBP1a/1b also bind RyRs and inhibits Ca2+-induced Ca2+ release, but it is not clear whether FKBPs act similarly in brain cells. Recently, we found that selectively disrupting hippocampal FKBP1b function in young rats, either by microinjecting adeno-associated viral vectors containing siRNA, or by treatment with rapamycin, increases the sAHP and recapitulates much of the hippocampal Ca2+ dysregulation phenotype. Moreover, in microarray studies, we found FKBP1b gene expression was downregulated in hippocampus of aging rats and early-stage Alzheimer’s disease subjects. These results suggest the novel hypothesis that declining FKBP function is a key factor in aging-related Ca2+ dysregulation in the brain and point to potential new therapeutic targets for counteracting unhealthy brain aging.

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Section: Neuronal Calcium (Ca2+) Dysregulation With Agingmentioning

confidence: 99%

FK506-binding protein 1b/12.6: A key to aging-related hippocampal Ca2+ dysregulation?

Gant

Blalock

Chen

et al. 2014

European Journal of Pharmacology

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“…Although in a separate study a change in the sAHP was not observed in pyramidal cells in a hAPP/PS1 Tg line, there was an increase in pyramidal excitability and altered sodium channel currents in these mice [37]. Interestingly, Thibault and colleagues [38] have recently reported a reduction in L-type calcium channel activity in the double knock-in hAPP/PS1 mice. These studies suggest that subtle changes in ion channel function are present in different AD Tg mouse lines that could impact on the ability of the network to generate network oscillations.…”

Section: Investigating the Causes Of Impaired Network Oscillationsmentioning

confidence: 93%

Cortical network oscillations in Alzheimer's disease: insights from rodent models

LeBeau

2013

Drug Discovery Today: Therapeutic Strategies

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“…The altered activities of these enzymes may contribute to abnormal neuronal circuit functioning in such neuropathological conditions (Ji et al, 2009). Impairment in Ca 2+ homeostasis is a common feature in Alzheimer's disease and other neurodegenerative disorders involving damage and death of neurons (Mattson, 2007;Bezprozvanny and Mattson, 2008;Thibault et al, 2012 (Gargus, 2009). …”

Section: +mentioning

confidence: 99%

Combined arsenic and di-(2-ethylhexyl) phthalate exposure elicits responses in brain ATPases different from hepatic and renal activities in rats

Afolabi¹,

Ugbaja²,

Ademuyiwa³

2016

J. Toxicol. Environ. Health Sci.

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Arsenic and di-(2-ethylhexyl) phthalate (DEHP) are environmentally ubiquitous and epidemiologically important toxic agents that millions of people are currently exposed to, worldwide. Although the adverse impact due to exposure to either arsenic or DEHP are documented, the toxicological effects of co-exposure to these agents are largely unknown. In this study, exposure to these chemicals was investigated for their effects on ATPase activities in the brain, liver and kidney of rats. Male Wistar rats were exposed daily to 100 mg L -1 arsenic via drinking water and to 100 mg DEHP kg -1 body weight in corn oil either individually or concurrently for 30 days. Toxicity was assessed by evaluating changes in body and organ weights, as well as, Na + /K + -, Ca 2+ -, Mg 2+ -and total ATPase activities in the brain, liver and kidney. Exposure to either arsenic or DEHP resulted in drastic reduction in activities of the enzymes in the compartments investigated, except in the brain where Na + /K + -and Mg 2+ -ATPases had their activities significantly increased. Also, DEHP displayed no effect on the total ATPase and Ca 2+ATPase in the kidney and brain, respectively. Interestingly, co-exposure to these toxicants significantly stimulated the activities of all these enzymes in the brain. In this compartment, combined treatment resulted in an additive interaction between the toxicants and a potentiation effect of arsenic on DEHP with regards to the Na + /K + -ATPase activity and Ca 2+ -ATPase activity, respectively. Our findings demonstrate tissue specific response to combined arsenic and DEHP exposure in rats with the effect on the brain significantly different from other compartments.

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Reduction in neuronal L-type calcium channel activity in a double knock-in mouse model of Alzheimer's disease

Cited by 38 publications

References 43 publications

FK506-binding protein 1b/12.6: A key to aging-related hippocampal Ca2+ dysregulation?

FK506-binding protein 1b/12.6: A key to aging-related hippocampal Ca2+ dysregulation?

Cortical network oscillations in Alzheimer's disease: insights from rodent models

Combined arsenic and di-(2-ethylhexyl) phthalate exposure elicits responses in brain ATPases different from hepatic and renal activities in rats

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