# Sleep abnormalities in Down Syndrome-related Alzheimer's disease

> **NIH NIH R01** · UNIVERSITY OF COLORADO · 2023 · $700,717

## Abstract

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-ind...

## Key facts

- **NIH application ID:** 10658057
- **Project number:** 1R01AG083268-01
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** CHARLES A HOEFFER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $700,717
- **Award type:** 1
- **Project period:** 2023-09-15 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10658057

## Citation

> US National Institutes of Health, RePORTER application 10658057, Sleep abnormalities in Down Syndrome-related Alzheimer's disease (1R01AG083268-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10658057. Licensed CC0.

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