Differentiating chronic sleep disruption from intermittent hypoxia in OSA on tau pathology and spread

About This Grant

Project Summary. Accumulating evidence suggests that Alzheimer’s disease (AD) has a long preclinical phase, lasting years to decades during which the accumulation of pathological proteins such as amyloid beta (Aβ) and tau can occur prior to the appearance of overt cognitive symptoms. Obstructive sleep apnea (OSA) is one of the most common sleep disorders and is composed of both sleep disruption (SD) and intermittent hypoxia (IH). Disentangling the separate contributions of chronic SD and chronic IH may reveal how OSA impacts risk for AD. While the effects of SD and IH on Aβ have been studied in both humans and animal models, less is known about the effects of SD and IH on tau spread and propagation throughout the brain, a crucial step in the formation of neurofibrillary tangles (NFT) throughout the brain. Our rationale for targeting tau stems from our own findings demonstrating significant associations between cerebrospinal fluid (CSF) concentrations of the wake-promoting neuropeptide orexin and both total and hyperphosphorylated tau, and that individuals with OSA might show signs of MCI and AD at a younger age. In addition, the treatment of OSA has been shown to delay the age of onset of MCI and to improve cognitive function in AD. Although these observations and others implicate OSA in the regulation of tau in the brain they do not establish directionality. A causal role for OSA in accelerating NFT formation would be strengthened by both chronic SD and chronic IH in mouse models of tauopathy and forms the basis for Aim 1. Given the association between tau and orexin, effective treatment of OSA holds particular promise in slowing the spread of tau throughout the brain. While hyperphosphorylation of tau is important in the formation of NFT’s, the development of AD may be separately accelerated by the spread of tau from neuron to neuron by particular aggregate conformations, a phenomenon that depends on activity of the seeding neuron. The locus coeruleus (LC) is a key brain region that expresses some of the earliest tau pathology, and importantly, the LC promotes wakefulness through rostral noradrenergic projections and is silent during sleep. Therefore, the increased neural activity of the LC during SD or IH represents a potential mechanism by which chronic SD affects the spread of tau pathology to rostral targets. Identifying the precise brain targets to which tau spreads from the LC and the time course over which this occurs is addressed in Aim 2. Addressing the hyperphosphorylation and spread of tau in models with and without LC specificity and the associated behavioral consequences on spatial, motor and fear learning as a function of chronic sleep disruption or chronic intermittent hypoxia serves as the basis for Aims 3.