Investigating a novel vascular pathway that regulates neuronal survival

Johns Hopkins University, Baltimore MD

Investigators

Abstract

Project Summary: Vascular abnormalities are associated with neurodegenerative diseases, including Alzheimer’s disease (AD), the AD-related dementia (ADRD) Amyotrophic Lateral Sclerosis (ALS)/Frontotemporal Dementia (FTD), and ALS. One mechanism contributing to neurodegeneration is the failure of the vasculature to release signaling factors that promote neuronal survival. Efforts to develop these factors as therapies have lapsed due to unwanted angiogenic effects upon delivery. Preliminary studies here identify a novel pathway in vascular endothelial cells that releases a protein required for neuronal survival with minimal angiogenic function. The six-transmembrane enzyme Glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) acts at the cell surface to cleave the glycosylphosphatidylinositol (GPI)-anchor that tethers some proteins to the membrane. GDE2 distribution and function are disrupted in ALS, ALS/FTD, and Alzheimer’s Disease but are not affected in Huntington’s disease (HD), suggesting some specificity of GDE2 dysfunction across neurodegenerative diseases. GDE2 is normally expressed in neurons, oligodendrocytes, and vascular endothelial cells. Genetic ablation of GDE2 in vascular endothelial cells, but not neurons or oligodendrocytes, results in spinal motor neuron loss. Further, conditioned medium from cultured vascular endothelial cells (veCM) from Gde2 knockout (KO) mice fails to rescue cell death in in vitro cell viability models. These observations suggest that GDE2 vascular function is required for neuronal survival. The GPI-anchored protein Glypican (GPC) 6 is a substrate of GDE2 that overlaps with GDE2 expression in vascular endothelial cells, is linked to ALS and Alzheimer’s Disease via GWAS, and shows abnormal expression and release in ALS models and postmortem brain of patients with ALS and the ADRD ALS/FTD. veCM from vascular endothelial cells with GPC6 knockdown has limited neuroprotective activity in cellular survival models, and genetic ablation of GPC6 in vascular endothelial cells leads to spinal motor neuron loss in vivo. Further, GPC6 delivery is sufficient to promote motor neuron survival in vitro and in vivo, with minimal angiogenic effects. These observations suggest the hypothesis that vascular GDE2 activity releases GPC6, which selectively acts on neurons to promote their survival, and that the disruption of this pathway contributes to neurodegenerative pathologies in disease. This proposal will test this hypothesis with three Aims. Aim 1 will determine if pro-survival roles for GDE2 vascular function apply to cortical areas and if its functions are neuro-selective. Aim 2 will define the mechanism of GPC6 neuroprotective function and assess its angiogenic activity. Aim 3 will determine if the failure of GPC6 release contributes to neurodegenerative changes using mouse models of ALS and the ADRD ALS/FTD. Outcomes from these studies are expected to provide new molecular insight into the physiological contributions of the vasculature to neuronal survival, which could clarify vascular-dependent involvement in disease pathogenesis in ALS, ADRDs, and Alzheimer’s Disease and identify new candidates for therapeutic development.