Targeting CNS LDLR to ameliorate tau-mediated neurodegeneration

Rationale:

Our group found that Apolipoprotein E (ApoE) particularly ApoE4 strongly increases tau-mediated neurodegeneration and that the absence of apoE is neuroprotective.  More recently, we have also found that increasing the expression of the low density lipoprotein receptor (LDLR) lowers apoE in the brain and also strongly decreases tau-mediated neurodegeneration.  We have found that specific compounds increase LDLR gene expression in a cellular assay.  Herein, we proposed to determine which of the most promising compounds increase LDLR protein expression and LDLR function in brain cells and then in vivo in mouse brain.

Drug Discovery Program Status:

We have identified 3 compounds that increase LDLR in brain cells in cultured cells and are in the process of determining their effects in the brain.

Executive Summary:

Tauopathies such as progressive supranuclear palsy, forms of frontotemporal dementia, chronic traumatic encephalopathy and Alzheimer disease are characterized by the accumulation of certain forms of aggregated, hyperphosphorylated tau in specific brain regions accompanied by neurodegeneration.  Our group found that Apolipoprotein E (ApoE) particularly ApoE4 strongly increases tau-mediated neurodegeneration and that the absence of apoE is neuroprotective.  More recently, we have also found that increasing the expression of the low density lipoprotein receptor (LDLR) lowers apoE in the brain and also strongly decreases tau-mediated neurodegeneration.  We developed a cellular assay to screen for compounds that increase expression of the LDLR gene.  We have discovered several compounds that increase LDLR gene expression.  Herein, we are validating which of these compounds increase LDLR protein expression and LDLR function in brain cells and then in vivo in mouse brain. For the most promising compounds, we will assess them in a mouse model of tauopathy.