Identification of ApoE-dependent lipid pathways in microglia and their regulation by long non-coding RNAs (lncRNAs) for brain-specific targeting of neurodegeneration in Alzheimer’s Disease (R-16099)

Dementia is predicted to affect 153 million people by 2050, with the majority suffering from Alzheimer’s disease (AD), with no cure available. Recently, putative protective ApoE were found to be associated with effectively delayed symptoms by decades. This provides a proof-of-concept for targeting ApoE to halt AD in humans. Direct ApoE targeting, however, is impossible as this leads to lipid disorders and cardiovascular disease. Here I aim to identify ApoE-dependent targets to inhibit disease progression, halting progressive Amyloid pathology, Tau pathology and neurodegeneration, or ATN progression, characteristic for AD. Based on previous and preliminary data, I will identify ApoE-dependent lipid pathways, conserved from mice to humans, that halt ATN progression, by halting homeostatic microglia conversion. This is performed by combined use of multi-omics and targeted approaches of ApoE-lipid pathways, in a validated murine ATN model, with ApoE-dependent ATN halting, in comparison with human data-sets, tissue, and in vitro models. Additionally, I will identify long non-coding RNAs (lncRNA) that modulate these lipid pathways, followed by in vitro and in vivo validation of ATN halting in the ATN model, as a basis for RNA based therapy. Hence I here aim to identify ApoE-dependent lipid pathways and their regulation by lncRNA, conserved from mice to humans, that halt ATN progression, to fill current knowledge gaps and as a basis for innovative RNA based therapies for AD.

Keywords:Alzheimer's disease, Amyloid pathology/tau pathology/neurodegeneration, Microglia

Disciplines:Lipids, Cell signalling, Neurological and neuromuscular diseases, Pathophysiology, Single-cell data analysis