Role of LRP in TGFβ2‐mediated neuronal uptake of Aβ and effects on memory

Abstract

There is increasing evidence that soluble amyloid-β peptide (Aβ) uptake into neurons is an early event in the pathogenesis of Alzheimer's disease (AD). Identification of the early events leading to neuronal dysfunction is key to developing therapeutic strategies, but relative roles of receptors and factors modulating uptake are poorly understood. Studies have shown that transforming growth factor β (TGFβ), particularly TGFβ2, can influence the targeting of Aβ to cells in vitro. TGFβ2 can target Aβ to neurons in organotypic hippocampal slice cultures (OHSC). We examine a specific mechanism for TGFβ2-mediated targeting of Aβ to neurons. The receptor-associated protein (RAP), a low-density lipoprotein receptor-related protein (LRP) antagonist, can attenuate the cellular targeting of Aβ both in vitro and in vivo and prevent Aβ/TGFβ2-induced memory retention deficits. Using both in vitro and in vivo methods, we identify LRP as playing a role in TGFβ2-mediated Aβ uptake, neurodegeneration, and spatial memory impairment.