GLP-1-estradiol as a novel treatment for cognitive decline with normal and metabolic aging

Alzheimer’s disease (AD) is a form of dementia that affects millions of people and has no effective treatment.

Non-modifiable major risk factors for AD include age, APOEε4 alleles and female sex, while modifiable risk factors include metabolic disturbances (e.g. obesity, diabetes).

A drug, combining anti-diabetic/anti-obesity hormone glucagon-like peptide-1 (GLP-1) with estradiol (GE), was recently developed as a treatment for metabolic disease.

In addition to glucoregulation and appetite reduction, both hormones also have beneficial effects against neurodegeneration and cognitive decline.

Our goal is to investigate GE as a novel AD treatment.AIM I: To examine whether GE improves cognition, neuroplasticity and cognitive decline in middle-age humanized apolipoprotein E (hAPOE) ε3 (standard isoform) and hAPOEε4 (model of sporadic AD), normal and overweight, male and female rats.AIM II: To elucidate if GE mediates its protective effects by reducing microglial activity, and thereby neuroinflammation, through actions within the hippocampus.The project combines my expertise on GLP-1 with Professor Galea’s (UBC) expertise on sex/sex hormone influence on neuroplasticity and AD, Professor Annie Ciernia’s (UBC) expertise on neuroinflammation, Brian Finan(Novo nordisk) expertise on GE, and will provide new insights for AD treatment development.