BSB PhD Exit Seminar: Investigating the potential for P-glycoprotein in the prevention of Alzheimer’s Disease

Abstract

Alzheimer’s Disease (AD) is a neurodegenerative disorder characterised by the deposition of Amyloid-β (Aβ) aggregates throughout the cerebrum, especially in the cerebrovascular and hippocampal tissues. Production of Aβ peptides is physiological and constant; however, the clearance of these peptides is impaired in the brain of Alzheimer’s patients. Studies suggest the multidrug efflux pump P-glycoprotein (P-gp) mediates the efflux of Aβ peptides from brain cells. Does functional P-gp allow the efficient clearance of Aβ peptides out of the central nervous system? Can ensuring the correct function of P gp prevent the development of dementia? The present study uses C. elegans models to investigate these questions. Using a transgenic line that expresses a type of Aβ peptides in the bodywall muscles of C. elegans, methods were established to characterize the dementia phenotype in the model organism. When the expression of human P-gp was induced in the same tissue, the dementia phenotype was assessed again and compared to both parental transgenic lines. It was found that expression of either the Aβ peptide or human P-gp alone caused age-dependent cognitive decline in C. elegans. In the transgenic model expressing both the Aβ peptide and P-gp together, the dementia phenotype was improved compared to the AD model. This indicates the potential of P-gp in the prevention of Aβ-related pathology. This study provides the first proof-of-concept that enhancing the P-gp mediated Aβ clearance pathway may produce cognitive benefits at a whole organism level. It shines a light on targeting P-gp for preventive treatments of AD.