Shannon L. Macauley, PhD is an Assistant Professor of Internal Medicine in the Section on Gerontology and Geriatric Medicine at Wake Forest University School of Medicine. She is also a member of the Sticht Center on Aging and Alzheimer’s Prevention and the Center for Diabetes, Obesity, and Metabolism. The main focus of Dr. Macauley’s work is to understand diseases of the central nervous system (CNS) and how secondary mechanisms, such altered CNS metabolism, impact neuronal health and function. Her work is focused in two main areas: 1) the interplay between Alzheimer’s disease (AD) and type-2-diabetes (T2D) and 2) the understanding and treatment of lysosomal storage diseases (LSDs). As it relates to the relationship between AD and T2D, the Macauley lab uses mouse models to understand how metabolic perturbations, either systemically or within the brain, affect the progression of AD-related pathology, such as the production, clearance, and aggregation of amyloid-beta (Aß) or tau. She uses a variety of methods, including glucose clamps, in vivo microdialysis, and neuroimaging techniques to study the acute effects of metabolic challenges on Aß dynamics within the brain’s interstitial fluid (ISF) as well as chronic studies to investigate what metabolic factors impact the progression of AD-related pathology and functional deficits. Ultimately, the goal is to leverage these findings as therapeutic targets for treating neurodegenerative disorders.

Shannon L. Macauley, PhD is an Assistant Professor of Internal Medicine in the Section on Gerontology and Geriatric Medicine at Wake Forest University School of Medicine. She is also a member of the Sticht Center on Aging and Alzheimer’s Prevention and the Center for Diabetes, Obesity, and Metabolism. The focus of her research is to understand diseases of the central nervous system (CNS) and how alterations in metabolism, vascular function, and sleep impact healthy brain function. Ultimately, the goal is to leverage these findings as therapeutic targets for treating CNS diseases, including Alzheimer’s disease and lysosomal storage diseases (LSDs). Her work focuses on two main areas: 1) metabolic dysfunction in Alzheimer’s disease (AD) and 2) treatment strategies for neurodegenerative disorders, including AD and LSDs. To study AD, her laboratory uses rodent models, non-human primates, and human data to understand how metabolic or vascular perturbations affect the progression of Alzheimer’s-related pathology. For rodent studies, the laboratory uses a variety of in vivo techniques, including glucose clamps, in vivo microdialysis, in vivo biosensors, EEG/EMG recordings, and small animal neuroimaging to study the acute effects of metabolic challenges on cerebral metabolism, neuronal activity, Aß/tau dynamics, and sleep. For chronic studies, the laboratory uses rodent models and non-human primates to investigate how Alzheimer’s disease risk factors, like metabolic dysfunction or sleep disruptions, impact Aß/tau pathology, learning and memory, cerebral metabolism, and brain network connectivity.

Previous work from the laboratory demonstrates that hyperglycemia, or elevations in blood glucose levels, are sufficient to increase neuronal activity and extracellular Aß levels in the hippocampus through the inhibition of inward rectifying, ATP-sensitive potassium (KATP) channels. This work was expanded from rodent models to a non-human primate model of naturally occurring type-2-diabetes to confirm that changes in blood glucose levels correlate with alterations plasma lactate, CSF Aß40, and CSF Aß42. This work illustrates a feed forward mechanism by which metabolic activity could drive neuronal activity to affect Alzheimer’s disease related pathology. Moreover, in humans, we found that acute disruption of slow wave activity in sleep correlated with increased CSF Aß40, suggesting this process is due to changes in neuronal activity. Therefore, current R01-funded work investigates the relationship between cerebral metabolism, neuronal activity, and sleep in AD. Moreover, the laboratory is exploring whether targeting metabolic changes due to disrupted sleep, Aß, or tau aggregation is sufficient to rescue sleep architecture and reduce Alzheimer’s related pathology.