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Author ORCID Identifier

https://orcid.org/0009-0008-2717-9393

Date Available

4-28-2026

Year of Publication

2026

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Medicine

Department/School/Program

Molecular and Cellular Biochemistry

Faculty

Michael Paul Murphy

Abstract

Alzheimer’s Disease (AD) is a complex neurodegenerative disease with two hallmark pathologies: extracellular amyloid-b (Ab) and intracellular neurofibrillary tangles (NFTs). Ab is proteolytically processed from amyloid precursor protein (APP) by b-secretase and g-secretase as a monomeric peptide prone to aggregation. Eventually, the aggregate-prone monomers will form dense plaques that are difficult to break down and remove. These plaques begin to deposit into the cortex decades prior to the formation of NFTs and the onset of cognitive decline. NFTs are comprised of hyper-phosphorylated tau. Tau is a protein that serves to promote and stabilize the formation of microtubules. The formation of NFTs in the brain corresponds to the onset of mild cognitive decline symptoms. Ab is believed to be a driver of NFT pathology, but a mechanism has not been established.

A circadian rhythm is an endogenous biological process found in different systems throughout the body, including the sleep-wake rhythm. Circadian rhythm dysfunction is a prominent factor in aggravating AD progression, and links between fragmented sleep, disrupted circadian rhythms, and AD are established, including how fragmented sleep is commonly seen in individuals with AD and in studies in AD-model mice.

Across three aims, circadian rhythm and sleep fragmentation studies were conducted to further explore the link between circadian rhythms, sleep, and AD. In the circadian rhythm studies, mice, half mutant AD-model, half wild-type (WT) counterparts, were acclimated to two weeks of a 12:12 light/dark cycle, followed by 24 hours of darkness. Afterwards, still in darkness, the brain tissue was collected every three hours for 24 hours. The sleep fragmentation studies included PS19, tau mutant mice and their WT counterparts: half had their sleep fragmented four times a day on weekdays for varying weeks, and the other half had unrestricted sleep. Activity was recorded using a piezo cage system. Tissues were pulverized and/or homogenized in extraction buffers to extract three protein pools: soluble, detergent-soluble, and acid-soluble. Samples of each fraction were tested and analyzed via immunoassays to quantitatively and qualitatively measure target proteins and RT-PCR to measure expression of APP and core clock genes at the transcriptional level.

In APPxPS1 knock-in (KI) mice, we found that soluble Ab shows an overall rhythm that peaks in the evening, when mice are typically awake and active, and troughs in the morning, when mice spend more time asleep and are less active. When looking at specific regions, this rhythm is weaker in the olfactory bulb and forebrain of the KI mice, compared to the WT mice, but similar in the cerebellum of both genotypes. The Ab precursor, APP, does not show an overall rhythm in most regions but, after splitting the genotypes, a rhythm is observed in female KI mice, particularly in the forebrain. APP mRNA expression has a significant rhythm in female KI and WT mice. Overall, core clock gene expression levels of BMAL1, Per1, and CIART all showed the expected circadian rhythm cycling; however, the rhythm of these genes was shifted when looking at specific genotypes or one of the sexes, showing that without experimental manipulation, AD-model mice with pathology will exhibit changes in their typical physiology. In sleep fragmentation studies, both PS19 and WT mice that experienced fragmented sleep showed increased APP and Ab, consistent with previous lab findings in a different AD mouse model. Sleep fragmentation had small effects on total and phosphorylated tau between regions, fractions, and genotypes.

Biological rhythms are important for multiple aspects of AD, and disruptive changes in these rhythms are a major factor in the disease process. These studies suggest that the primary consequence of sleep and rhythm disruption is not necessarily on the amounts of either tau or Aβ, but may lie in other rhythmic proteins.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2026.148

Archival?

Archival

Funding Information

This study was supported by National Institutes of Health grants AG068215 and AG068215-03S1.

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