Sunday, May 18, 2025
5/18/2025
Sleep abnormalities in Down Syndrome-related Alzheimer's disease - PROJECT ABSTRACT The NIH INCLUDE initiative focuses on critical health and quality-of-life needs for individuals with Down syndrome (DS). Part of this mission is “to conduct targeted, high-risk, high-reward basic science studies on chromosome 21.” In addition, the NIA is prioritizing research that aims “to understand the molecular mechanism(s) underlying the interplay between aging and neurodegeneration in DS”. This proposal addresses these goals by DS-AD links in sleep disturbances in DS individuals. Connections between Alzheimer’s disease (AD) and DS are well-documented, but the mechanisms underlying them are little understood. A strong candidate is the cleavage product of Amyloid Precursor Protein (APP), Aβ, a defining histopathological marker of AD which promotes sleep dysfunction. Another candidate trisomy21 gene, Regulator of Calcineurin1 (RCAN1), affects circadian function and promotes AD-related pathology. This proposal focuses on APP and RCAN1 overexpression as mechanistic links between DS and AD-related disease involved in sleep disruption, circadian dysregulation, cognition impairment, and synaptic deficits. Our preliminary data demonstrate that genetic manipulation to restore Rcan1 to normal levels rescues sleep disturbances in a DS model. Therefore, our central hypothesis is that RCAN1 triplication in DS promotes sleep disturbances and exacerbates AD- related pathology. However, because APP and Aβ42 disrupt sleep and induce cognitive deficits, we will also assess the role of APP overexpression in DS sleep disturbances. Specifically, we will: 1) determine the effects of App and Rcan1 gene dosage correction on age-dependent sleep disruption and circadian clock expression in DS model mice; 2) quantify the effects of Rcan1 gene dosage correction on age-dependent synaptic deficits and network firing properties in DS model neurons; and 3) leverage the power of transcriptome analyses to infer molecular mechanisms underlying sleep disruption in Dp16 mice. Outcome measures for the proposal include sleep and circadian behavioral assessments; hippocampal slice electrophysiology; multi-electrode array (MEA) recordings in DS-derived neuronal culture; unbiased transcriptome analyses; cytokine protein assays; and immunohistochemical evaluation of glial activation and pathological tau. Our approach is conceptually and technically innovative because the role of APP and/or RCAN1 have not been formally considered in DS-AD-linked sleep abnormalities. Also, MEA methods not been used to study sleep in a DS model. This study is significant because, despite the links we have articulated, the role of APP or RCAN1 overexpression in promoting DS-related sleep or cognitive abnormalities has not been investigated. Data from the successful completion of this project will begin to fill a critical knowledge gap by determining how APP/RCAN1expression influences sleep disturbances and progression of AD-like pathology in DS. Importantly, data implicating APP/RCAN1-induced neuroinflammatory processes would suggest potential therapeutic avenues that could improve sleep quality or slow disease progression in DS individuals.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).