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-␤ (A␤) disrupts hypothalamic neurons critical for the regulation of body weight. We previously reported that, in young transgenic mice overexpressing mutated amyloid precursor protein (Tg2576), A␤ causes dysfunction in neuropeptide Y (NPY)-expressing hypothalamic arcuate neurons before plaque formation. In this study, we examined whether A␤ causes arcuate NPY neuronal dysfunction by disrupting intracellular Ca 2ϩ homeostasis. Here, we found that the L-type Ca 2ϩ channel blocker nimodipine could hyperpolarize the membrane potential, decrease the spontaneous activity, and reduce the intracellular Ca 2ϩ 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 Ca 2ϩ currents, resulting in increased Ca 2ϩ influx closer to the resting membrane potential, an effect recapitulated by A␤ 1-42 and reversed by nimodipine. These low voltage-threshold activated L-type Ca 2ϩ currents were dependent in part on calcium/calmodulin-dependent protein kinase II and IP 3 pathways. Furthermore, the effects on intracellular Ca 2ϩ 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 Ca 2ϩ dysregulation is only reversible early in A␤ pathology. Collectively, these findings provide evidence for a key role for low-threshold activated voltage gated L-type Ca 2ϩ channels in A␤-mediated neuronal dysfunction and in the regulation of body weight.

Heightened β-adrenergic receptor function in the TgF344-AD rat model drives synaptic potentiation and supports learning and memory

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Mitochondrial Calcium Deregulation in the Mechanism of Beta-Amyloid and Tau Pathology

“…Tau and β-amyloid-induced Ca 2+ dysfunction through VGCCs have been described in different models of AD and tau-induced FTD [ 86 , 87 ]. We have recently shown that in vitro aggregated tau fibrils with the P301S mutation linked to FTD are able to incorporate into membranes and modify their ionic currents, as seen by BLM experiments [ 69 ].…”

Structure and therapeutic uses of butyrylcholinesterase: Application in detoxification, Alzheimer's disease, and fat metabolism

“…Weight loss is a common symptom in AD patients, which is even earlier than impairments of cognitive functions 236 . It was also reported that weight gain might be protective against dementia, 237 but it is difficult for AD patients due to the poor mental states.…”

“…Loss of appetite and behavioral eating disorders could be observed in more than 80% AD patients, ranging from mild to severe, which exerted a great influence on treating and nursing care 239,240 . In 2019, Ishii et al 237 pointed out the relationship between early weight loss of AD patients and the arcuate neuropeptide Y neurons, the latter of which was related to food‐intake. The neurons were supposed to be impaired by Aβ through being disrupted intracellular Ca 2+ homeostasis, which led to a blunt response to ghrelin and therefore loss of appetite.…”