Alzheimer's Disease and Type-2-Diabetes

The focus of my lab is to understand diseases of the central nervous system (CNS) and how secondary mechanisms, such altered CNS metabolism, impact neuronal health and function.  Ultimately, the goal is to leverage these findings as therapeutic targets for treating neurodegenerative disorders.  Our 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).

Patients with T2D have an increased risk for AD.  Hyperglycemia, hyperinsulinemia, and insulin resistance have all been linked to dementia and dementia of an Alzheimer’s type. Therefore, we explore how key features of T2D, such as alterations in glucose and insulin, affect the hallmarks of AD pathology, including amyloid-β (Aβ) and tau production, aggregation, and accumulation.  Hyperglycemia alone can affect human cognitive function, default mode network processing, and spontaneous brain activity, suggesting that disrupted glucose homeostasis affects neurodegenerative processes associated with cognitive dysfunction and AD. Our research demonstrates that hyperglycemia modulates extracellular concentrations of amyloid-β (Aβ) in an activity-dependent manner through KATP channel activity.  Using methods that couple in vivo microdialysis and glucose clamps in animal models of AD, current work focuses on how hyperglycemia affects neuronal activity, synaptic plasticity and network connectivity in the context of healthy aging and AD pathology.  We also continue to explore the role of the KATP channel activity in AD, both in terms of disease pathogenesis and therapeutic intervention. In concert, we are investigating how peripheral or CNS-directed hyperinsulinemia affects insulin signaling and Aβ levels within the brain in order to further understand the complex relationship between T2D and AD. Given my interest in CNS metabolism, we are currently investigating why regions prone to Aβ deposition are more metabolically active, resulting in a unique metabolic signature compared to other regions in the brain.  Not only has this been observed in human patients with AD, it is seen in mouse models of cerebral amyloidosis.  We recently found that alterations in key glycolytic enzymes involved in aerobic glycolysis are altered as a function of age and Aβ, impacting learning and memory differentially.

 

In addition to my interests in T2D and AD, we study mechanisms of neurometabolism, neurodegeneration, and neuroinflammation in lysosomal storage diseases (LSD) and how targeting different aspects of pathology with combination therapies enhances efficacy.  Our findings not only characterized the temporal-spatial spread of CNS disease and functional deficits in mouse models of Niemann-Pick Type A, infantile neuronal ceroid lipofuscinosis, Pompe disease, Krabbe disease, and late-infantile neuronal ceroid lipofuscinosis, but also identified secondary disease mechanisms associated with neurodegeneration that need to be addressed in treatment strategies for these disorders.

Funding

  • NIA R01 AG061805 (CoI)

  • NIA R01 AG065839 (CoI)

  • WF-TARC Pilot Grant (PI)

  • ADRC Pilot Grant (PI)

  • CTSI Pilot Grant (CoI)

  • New Vision Award through Donors Cure Foundation (PI)

  • NIA K01 AG050719 (PI)

  • NINDA F32 NS080320 (PI) 

  • McDonnell Center for Systems Neuroscience Small Grant (PI: Macauley/Bauer)

  • P01 NS080675 (Raichle/Holtzman/Hershey/Culver)

The Macauley Lab | Wake Forest School of Medicine

575 N. Patterson Avenue | Winston-Salem, NC 27101

smacaule@wakehealth.edu 336.716.4628

macauleylab.com | @macauleylab