Network changes and compensation mechanisms of wake‐promoting neurons across AD continuum

Abstract

AbstractBackgroundSleep is a complex process regulated by various neural mechanisms, including those promoting wakefulness, those promoting sleep, and those regulating the circadian clock. Recent research has revealed that wake‐promoting neurons, specifically those found in the noradrenergic locus ceruleus (LC), the orexinergic (ORX) neurons in the lateral hypothalamic area (LHA), and the histaminergic neurons in the hypothalamic tuberomammillary nucleus (TMN), are particularly vulnerable to the AD‐tau pathology found in the early stages of Alzheimer’s disease (AD). These studies have uncovered how these neurons accumulate AD‐tau, the extent to which they die in AD, and specific correlations with polysomnographic readings. Notably, a complex pattern of neuronal dysregulation within and among these wake‐promoting neurons has been observed, suggesting the existence of robust compensatory mechanisms in an attempt to overcome dysfunction. Thus, understanding the vulnerability of these nuclei to AD requires network‐based studies. These studies are crucial for informing disease‐specific treatment for sleep disturbance and identifying factors underlying the vulnerability of these neurons.MethodsResults from several ongoing experiments in the Grinberg Lab, including methods such as quantitative pathology, molecular profiling and clinicopathological correlationResultsFor example, the hypocretin (orexin) receptor 1 (HCRTR1) shows upregulation in orexin neurons from early AD stages, while no changes are observed in the LC or TMN. Additionally, while the LC shows an early pattern of upregulation of genes associated with neuroinflammation, early dysregulation in the ORX is related to synapse‐related genes. Furthermore, circadian genes such as CRY1 and CRY2 show upregulation in the ORX but downregulation in the TMN during AD progression.ConclusionThis talk will focus on current knowledge, including unpublished data, based on studies in humans, on the vulnerability of wake‐promoting neurons in AD, with a particular emphasis on similarities and contrasts in the patterns of dysregulation among these nuclei during AD progression, in conjunction with changes in the suprachiasmatic nucleus, the circadian clock, and regional expression of circadian genes.