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 Aβ_1-42 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.

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