The Sigma-2 Receptor/TMEM97, PGRMC1, and LDL Receptor complex are responsible for the cellular uptake of Aβ42 and its protein aggregates

Background: Our lab has recently shown that the Sigma-2 Receptor/Transmembrane Protein 97 (TMEM97) and Progesterone Receptor Membrane Component 1 (PGRMC1) form a complex with the Low Density Lipoprotein Receptor (LDLR), and this intact complex is required for efficient uptake of lipoproteins such as LDL and apolipoprotein E (apoE). These receptors are expressed in the nervous system where they have implications in neurodegenerative diseases such as Alzheimer's Disease (AD), where apoE is involved in neuronal uptake and accumulation of A{beta}42, eventually cascading into neurodegeneration, synaptic dysfunction, and ultimately, dementia. Hypothesis: We hypothesize that the intact Sigma-2 receptor complex - TMEM97, PGRMC1, and LDLR - is necessary for internalization of apoE and A{beta}42 monomers (mA{beta}42) and oligomers (oA{beta}42), and the disruption of the receptor complex inhibits uptake. Results: The results of this study suggest that the intact Sigma-2 receptor complex is a binding site for mA{beta}42 and oA{beta}42, in the presence or absence of apoE2, apoE3, and apoE4. The loss or pharmacological inhibition of one or both of these proteins results in the disruption of the complex leading to decreased uptake of mA{beta}42 and oA{beta}42 and apoE in primary neurons. Conclusion: The TMEM97, PGRMC1, and LDLR complex is a pathway for the cellular uptake of A{beta}42 via apoE dependent and independent mechanisms. This study suggests that the complex may potentially be a novel pharmacological target to decrease neuronal A{beta}42 internalization and accumulation, which may represent a new strategy for inhibiting the rate of neurotoxicity, neurodegeneration, and progression of AD.