# Alzheimer's disease pathogenesis and the desynchronization of cortico-limbic circadian rhythms

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2020 · $694,500

## Abstract

Recent work has established a clear connection between Alzheimer’s disease (AD) and the disruption of the
circadian timing system. However, the mechanistic underpinnings of this relationship have not been clearly
identified. Interestingly, if we attempt to deconstruct this relationship and place it within the context of the
profound effects that Alzheimer’s disease has on cognition, several ideas begin to come into focus. First, data
to date has revealed that circadian timing within cortico-limbic circuits modulates complex behavioral states,
including cognition. Second, AD has marked effects on functional plasticity of these same circuits. These
observations raise an interesting question: could the cognitive deficits in AD result, in part, from the
dysregulation of circadian timing within cortico-limbic circuits? As an initial examination of this idea, we
propose to test the following hypothesis: The cognitive deficits during early- to mid-stage of AD results in part from
a systems-wide breakdown in the fidelity of the cortico-limbic circadian timing systems. To test this hypothesis, we
have assembled an innovative set of transgenic mouse models and state-of-the-art imaging methods that will
allow us to both profile and manipulate circadian timing over the course of disease progression. In Aim 1, the
effects of amyloid β peptide (Aβ) on the fidelity of cellular-and circuit-based time-keeping capacity will be
examined. In Exp. 1A, we will use a cell-culture based profiling approach to test the effects of Aβ oligomer on
the cell autonomous circadian timekeeping capacity of neurons isolated from the SCN (the locus of the master
circadian clock), the cortex and the hippocampus. In Exp. 1B brain slice explant imaging will be used to test
the effects of Aβ on circuit-based circadian rhythm generation. In Aim 2 we propose to profile clock timing and
clock-gated gene expression in the 5XFAD mouse model of AD. In Exp. 2A, cranial window imaging (via
multiphoton microscopy) of clock timing in the frontal cortex and the hippocampus will be used to generate a
cellular- and systems-level profile of clock phasing, rhythm amplitude and oscillator synchrony over the
course of the AD-like pathology. This study will be complemented by immunofluorescence-based clock gene
profiling (Exp. 2B) and by transcriptomic profiling (Exp. 2C). In Aim 3, we will test the effects that disease
progression in the 5XFAD model has on clock-gated (Exp. 3A) and activity-evoked (Exp. 3B) cellular signaling,
as well as on dendritic spine formation. In Aim 4 we will test whether the desynchronization of cortico-limbic
oscillators underlies the cognitive deficits in the 5XFAD mouse model of AD. Key to this aim will be to test
whether the clock enhancing compound PF-670462 triggers the resynchronization of cortico-limbic oscillator
populations, and if so, whether this effect underlies the capacity of PF-670462 to augment cognition. If our
underlying hypothesis is validated, these data wi...

## Key facts

- **NIH application ID:** 10053947
- **Project number:** 1R01AG065830-01A1
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** KARI RENE HOYT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $694,500
- **Award type:** 1
- **Project period:** 2020-08-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10053947

## Citation

> US National Institutes of Health, RePORTER application 10053947, Alzheimer's disease pathogenesis and the desynchronization of cortico-limbic circadian rhythms (1R01AG065830-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10053947. Licensed CC0.

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