The Metabolic-Microvascular Maladaptation Pathway in Alzheimer's Disease

We focus on deciphering causes and mediators of impaired oxygen and glucose signaling at the blood-capillary-parenchyma interfaces in the brains of individuals with Alzheimer's disease (AD) with the goal of finding modalities to reverse hypoxic-ischemic brain injury and reduce the progression of disease.

Specific aims:
1. Identify key molecules, cells and genes involved in blood-capillary-parenchyma dysfunction in AD by using human specimens paired with clinical data;
2. Based on insights from studies in humans, define mechanisms and specific sex differences underlying blood-capillary-parenchyma dysfunction by using (or generating and investigating) appropriate animal models of AD;
3. Investigate functional outcome(s) of dietary interventions on oxygen and glucose sensing and delivery in animal models with genetically/ pharmacologically-modified blood-capillary-parenchyma function;
4. Use findings derived from laboratory experiments as a potential translation platform for drug development or combined diet-drug interventions in preparation for human studies targeting blood-capillary-parenchyma dysfunction in AD.

Collaborations in the US:
1. Department of Gerontology and Geriatric Medicine, Wake Forest School of Medicine;
2. Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids;
3. Department of Medicine, Division of Renal Diseases & Hypertension, The George Washington University School of Medicine & Health Sciences, Washington;
4. Memory & Brain Wellness Center, University of Washington, Seattle;
5. Department of Neuroscience, University of Chicago;
6. Department of Pharmacology, University of California, Davis;
7. Department of Internal Medicine, McGovern Medical School at UT Health, Houston;
8. Department of Pharmacology, University of North Carolina, Chapel Hill;
9. Cardiovascular Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

International Collaborations:
1. UK Dementia Research Institute at University College London, UK;
2. Department of Physiology, Development and Neuroscience University of Cambridge;
3. Department of Physiology, University of Oxford, UK;
4. Department of Neurology, University Medical Center Utrecht, The Netherlands;
5. Cliniques Universitaires Saint-Luc, Department of Medicine, Brussels, Belgium;
6. Université Catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle d'Endocrinologie, Diabète et Nutrition, Louvain la Neuve, Belgium;
7. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden;
8. Department of Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.