Neuronal LRP1 Knockout in Adult Mice Leads to Impaired Brain Lipid Metabolism and Progressive, Age-Dependent Synapse Loss and Neurodegeneration

• DOI: 10.1523/jneurosci.4067-10.2010
• Publication Date: 2010-12-15T18:02:17Z
• Authors: Qiang Liu; Justin Trotter; Juan Zhang; Melinda M. Peters; Hua Cheng; Jianxin Bao; Xianlin Han; Edwin J. Weeber; Guojun Bu
• Keywords: LRP1; Forebrain

The vast majority of Alzheimer's disease (AD) cases are late onset with progressive synapse loss and neurodegeneration. Although the amyloid hypothesis has generated great insights into mechanism, several lines evidence indicate that other risk factors might precondition brain to toxicity. Here, we show deletion a major lipoprotein receptor, low-density receptor-related protein 1 (LRP1), in forebrain neurons mice leads global defect lipid metabolism characterized by decreased levels cholesterol, sulfatide, galactosylceramide, triglyceride. These deficits correlate progressive, age-dependent dendritic spine degeneration, loss, neuroinflammation, memory eventual We further glutamate receptor subunits NMDA Glu selectively reduced LRP1 knock-out knockdown neurons, which is partially rescued restoring neuronal cholesterol. Together, these studies support critical role for maintaining homeostasis associated synaptic integrity, provide important pathophysiological mechanisms AD.