Final Report Summary - BEYOND (METABOLIC BASIS OF NEURODEGENERATIVE DISEASE)
Age-related dementia, such as Alzheimer’s disease (AD) are a health problem affecting millions of patients world-wide. Disturbingly, common disorders of the metabolism, such as diabetes and obesity emerge as major risk factors for AD, causally linking two health problems of epidemic proportions. The molecular mechanisms whereby disorders promote AD are poorly understood, a deficit that hampers successful implementation of therapeutic strategies to address these diseases. Now, work in BeyOND has identified pathways central to our understanding of the metabolic basis of AD. In interdisciplinary collaboration of scientists and clinicians with experts from industry, we have functionally characterized a novel familial disease gene of early onset AD encoding the receptor SORLA and we documented its mode of action in both neurodegeneration and body weight control and obesity. We identified the major lipoprotein receptor in the brain, called sortilin, and we elucidated the role of this receptor in neuronal lipid metabolism and the relevance of this pathway to explain the risk of AD seen with gene variants in lipid homeostasis. Furthermore, we uncovered the mode of action of two receptors, called SORCS1 and SORCS3 that are associated with diabetes and AD in patients. Our latter studies documented pathways whereby the brain controls systemic metabolism and feeding behavior and why alterations in these pathways may cause an imbalance in energy homeostasis. In addition to our scientific achievements, work in BeyOND has generated important research tools, such as novel protocols and human cell models of metabolic and neurodegenerative diseases that will further advance research efforts by many to study the metabolic causes of age-related dementia.