Does extracellular tau modulate neurogenesis via LRP1?

About This Grant

Project Summary/Abstract In Greek mythology, Mnemosyne is the Titan goddess of memory. The idea of memory as Titan likely stems from our cultural understanding of how memory helps form the core of a person’s personality, experience, and perspective. This is also one reason that loss of memory can be so devastating--it is especially prevalent amongst people who suffer from Alzheimer’s disease and other dementias; this neurodegenerative disease strips people of much of what they were. We have discovered a new player in the brain’s ability to retain memory: the protein LRP1 (low-density lipoprotein receptor related protein 1). We think understanding LRP1 will lead to exciting and novel insights into how patients with Alzheimer’s disease lose their memory. The brain has some capacity to regenerate due to a small population of neural stem cells. These neural stem cells are also fundamental in allowing the brain to retain memory. In Alzheimer’s disease and related dementias, patients lose neural stem cells. We have discovered that if we remove LRP1 from neural stem cells in adult mice, the mice show signs of significant memory impairment and altered neurogenesis, similar to mouse models of Alzheimer’s disease. Others have discovered that LRP1 plays a role in Alzheimer’s disease by interacting with proteins we already know cause disease in the brain, including amyloid beta, ApoE4, and most recently tau. Extracellular tau is particularly interesting due to its pathological, prion-like spread in the brain, which is facilitated by LRP1. What is not yet understood is whether extracellular tau can exert any physiological role, particularly on those processes which regulate neurogenesis to impact hippocampal memory function. This exploratory/developmental grant is designed to test the hypothesis that tau modulates neurogenesis through LRP1 in adult-born granule neurons. Our preliminary studies find that loss of LRP1 in adult-born hippocampal neurons cause phenotypes similar to those of tau knockout mice, including increased mature, adult- born granule neurons in LRP1 knockout cells and increased survival of developing neurons. Mature LRP1 knockout neurons displayed reduced dendritic branching. In the hippocampus, we expect that increases in extracellular tau alters neurogenesis to influence learning and memory via LRP1. Aim 1 will test the LRP1- dependent effects of extracellular tau on development of adult-born hippocampal neurons. Aim 2 will test whether rescuing LRP1 in adult-born hippocampal neurons rescues dendritic complexity in a tau- dependent manner. We will test our hypotheses via a combination of in vitro cell culture approaches with in vivo histological tests in our mouse model that allows knockout of LRP1 in adult neural stem cells, combined with tau knockout or infusion. We expect to leverage existing tools to enhance understanding of LRP1 in neurogenesis and Alzheimer’s disease, and by extension reduce the burden of this disease.