Amyloid-beta modulates low-threshold activated voltagegated l-type calcium channels of arcuate neuropeptide y neurons leading to calcium dysregulation and hypothalamic dysfunction

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Abstract

Weight loss is an early manifestation of Alzheimer's disease that can precede the cognitive decline, raising the possibility that amyloid-β (Aβ) disrupts hypothalamic neurons critical for the regulation of body weight. We previously reported that, in young transgenic mice overexpressing mutated amyloid precursor protein (Tg2576), Aβcauses dysfunction in neuropeptide Y (NPY)-expressing hypothalamic arcuate neurons before plaqueformation. Inthis study,we examinedwhether Aβcauses arcuateNPY neuronal dysfunction by disrupting intracellular Ca 2β homeostasis. Here, we found that the L-type Ca 2β channel blocker nimodipine could hyperpolarize the membrane potential, decreasethe spontaneous activity, and reducethe intracellular Ca 2β levels in arcuate NPY neuronsfrom Tg2576 brain slices. In these neurons, there was a shift from high to low voltage-threshold activated L-type Ca 2β currents, resulting in increased Ca 2β influx closer to the resting membrane potential, an effect recapitulated by Aβ1-42 and reversed by nimodipine. These low voltage-threshold activated L-type Ca 2β currents were dependent in part on calcium/calmodulin-dependent protein kinase II and IP3 pathways. Furtherβmore, the effects on intracellular Ca 2β signaling by both a positive (ghrelin) and negative (leptin) modulator were blunted in these neurons. Nimodipine pretreatment restoredthe responseto ghrelin-mediatedfeeding in young (3-5 months), but not older (10 months), female Tg2576 mice, suggestingthat intracellular Ca 2β dysregulation is only reversible early in Aβpathology. Collectively,thesefindings provide evidencefor a key rolefor low-threshold activated voltage gated L-type Ca 2β channels in Aβ-mediated neuronal dysfunction and in the regulation of body weight.

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Ishii, M., Hiller, A. J., Pham, L., McGuire, M. J., Iadecola, C., & Wang, G. (2019). Amyloid-beta modulates low-threshold activated voltagegated l-type calcium channels of arcuate neuropeptide y neurons leading to calcium dysregulation and hypothalamic dysfunction. Journal of Neuroscience, 39(44), 8816–8825. https://doi.org/10.1523/JNEUROSCI.0617-19.2019

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