Abstract

Circadian disruption has long been appreciated as a downstream consequence of Alzheimer’s Disease in humans. However, an upstream role for circadian disruption in regulating AD pathology remains an open question. The mammalian circadian system is hierarchical, with cellular clocks – driven largely by BMAL1 – synchronized by the hypothalamic SCN (suprachiasmatic nucleus) via a combination of hormonal and synaptic cues. To assess the relative contributions of each component to Alzheimer’s Disease pathology, we crossed mice harboring either microglial (Cx3cr1/Lyz2-Cre) or GABAergic (VGAT-iCre, expressed in more than 95% of the SCN) BMAL1-knockout to mouse models of Aβ aggregation (5xFAD; APP/PS1-21), which is thought to be the initiating event in AD pathogenesis. Ablation of BMAL1 in microglia failed to consistently alter plaque aggregation, suggesting that the myeloid circadian clock is dispensable for parenchymal Aβ accumulation. In contrast, inhibitory BMAL1-knockout using VGAT-iCre disrupted rhythmic behavior, physiology, and Aβ processing in a light-dependent manner, resulting in reduced plaque load and plaque-associated phospho tau. These studies shed light on the respective roles of microglial and GABAergic circadian clocks in mediating the molecular pathogenesis of AD, and they suggest a reevaluation of the proposed positive feedback loop between circadian rhythm disruption and Alzheimer’s Disease pathology.

Committee Chair

Erik Musiek

Committee Members

Albert Davis; Celeste Karch; Erik Herzog; Jeff Haspel

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

7-30-2025

Language

English (en)

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