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

Weight loss is an early manifestation of Alzheimer's disease that can precede the cognitive decline, raising the possibility that amyloid-ß (Aß) disrupts hypothalamic neurons critical for the regulation of body weight. We previously reported that, in young transgenic mice overexpressing mutated amyloid precursor protein (Tg2576), Aß causes dysfunction in neuropeptide Y (NPY)-expressing hypothalamic arcuate neurons before plaque formation. In this study, we examined whether Aß 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 Aß1-42 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 Aß pathology. Collectively, these findings provide evidence for a key role for low-threshold activated voltage gated L-type Ca2+ channels in Aß-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-ß is hypothesized to be critical for the early neuronal dysfunction driving AD pathogenesis. Here, we demonstrate that amyloid-ß 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-ß pathology. These findings highlight a novel mechanism of amyloid-ß-mediated neuronal dysfunction through L-type Ca2+ channels and the importance of these channels in the regulation of body weight.

Disorders of Body Weight, Sleep and Circadian Rhythm as Manifestations of Hypothalamic Dysfunction in Alzheimer's Disease.

While cognitive decline and memory loss are the major clinical manifestations of Alzheimer's disease (AD), they are now recognized as late features of the disease. Recent failures in clinical drug trials highlight the importance of evaluating and treating patients with AD as early as possible and the difficulties in developing effective therapies once the disease progresses. Since the pathological hallmarks of AD including the abnormal aggregation of amyloid-beta (Aß) and tau can occur decades before any significant cognitive decline in the preclinical stage of AD, it is important to identify the earliest clinical manifestations of AD and elucidate their underlying cellular and molecular mechanisms. Importantly, metabolic and non-cognitive manifestations of AD such as weight loss and alterations of peripheral metabolic signals can occur before the onset of cognitive symptoms and worsen with disease progression. Accumulating evidence suggests that the major culprit behind these early metabolic and non-cognitive manifestations of AD is AD pathology causing dysfunction of the hypothalamus, a brain region critical for integrating peripheral signals with essential homeostatic physiological functions. Here, we aim to highlight recent developments that address the role of AD pathology in the development of hypothalamic dysfunction associated with metabolic and non-cognitive manifestations seen in AD. Understanding the mechanisms underlying hypothalamic dysfunction in AD could give key new insights into the development of novel biomarkers and therapeutic targets.

Apoε4 disrupts neurovascular regulation and undermines white matter integrity and cognitive function.

The ApoE4 allele is associated with increased risk of small vessel disease, which is a cause of vascular cognitive impairment. Here, we report that mice with targeted replacement (TR) of the ApoE gene with human ApoE4 have reduced neocortical cerebral blood flow compared to ApoE3-TR mice, an effect due to reduced vascular density rather than slowing of microvascular red blood cell flow. Furthermore, homeostatic mechanisms matching local delivery of blood flow to brain activity are impaired in ApoE4-TR mice. In a model of cerebral hypoperfusion, these cerebrovascular alterations exacerbate damage to the white matter of the corpus callosum and worsen cognitive dysfunction. Using 3-photon microscopy we found that the increased white matter damage is linked to an enhanced reduction of microvascular flow resulting in local hypoxia. Such alterations may be responsible for the increased susceptibility to hypoxic-ischemic lesions in the subcortical white matter of individuals carrying the ApoE4 allele.