Amyloid-Beta Modulates Low-Threshold Activated Voltage-Gated L-Type Calcium Channels of Arcuate Neuropeptide Y Neurons Leading to Calcium Dysregulation and Hypothalamic Dysfunction

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), Aβ causes dysfunction in neuropeptide Y (NPY)-expressing hypothalamic arcuate neurons before plaque formation. In this study, we examined whether Aβ causes arcuate NPY neuronal dysfunction by disrupting intracellular Ca2+ homeostasis. Here, we found that the L-type Ca2+ channel blocker nimodipine could hyperpolarize the membrane potential, decrease the spontaneous activity, and reduce the intracellular Ca2+ levels in arcuate NPY neurons from Tg2576 brain slices. In these neurons, there was a shift from high to low voltage-threshold activated L-type Ca2+ currents, resulting in increased Ca2+ influx closer to the resting membrane potential, an effect recapitulated by Aβ1–42 and reversed by nimodipine. These low voltage-threshold activated L-type Ca2+ currents were dependent in part on calcium/calmodulin-dependent protein kinase II and IP3 pathways. Furthermore, the effects on intracellular Ca2+ signaling by both a positive (ghrelin) and negative (leptin) modulator were blunted in these neurons. Nimodipine pretreatment restored the response to ghrelin-mediated feeding in young (3–5 months), but not older (10 months), female Tg2576 mice, suggesting that intracellular Ca2+ dysregulation is only reversible early in Aβ pathology. Collectively, these findings provide evidence for a key role for low-threshold activated voltage gated L-type Ca2+ channels in Aβ-mediated neuronal dysfunction and in the regulation of body weight. SIGNIFICANCE STATEMENT Weight loss is one of the earliest manifestations of Alzheimer s disease (AD), but the underlying cellular mechanisms remain unknown. Disruption of intracellular Ca2+ homeostasis by amyloid-β is hypothesized to be critical for the early neuronal dysfunction driving AD pathogenesis. Here, we demonstrate that amyloid-β causes a shift from high to low voltage-threshold activated L-type Ca2+ currents in arcuate neuropeptide Y neurons. This leads to increased Ca2+ influx closer to the resting membrane potential, resulting in intracellular Ca2+ dyshomeostasis and neuronal dysfunction, an effect reversible by the L-type Ca2+ channel blocker nimodipine early in amyloid-β pathology. These findings highlight a novel mechanism of amyloid-β-mediated neuronal dysfunction through L-type Ca2+ channels and the importance of these channels in the regulation of body weight.