The sigma-2 receptor was originally defined pharmacologically and recently identified as TMEM97. TMEM97 has been validated as a biomarker of proliferative status and the radioligand of TMEM97, [¹⁸F]ISO-1, has been developed and validated as a PET imaging biomarker of proliferative status of tumors and as a predictor of the cancer therapy response. [¹⁸F]ISO-1 PET imaging should be useful to guide treatment for cancer patients. TMEM97 is a membrane-bound protein and localizes in multiple subcellular organelles including endoplasmic reticulum and lysosomes. TMEM97 plays distinct roles in cancer. It is reported that TMEM97 is upregulated in some tumors but downregulated in other tumors and it is required for cell proliferation in certain tumor cells. TMEM97 plays important roles in cholesterol homeostasis. TMEM97 expression is regulated by cholesterol-regulating signals such as sterol depletion and SREBP expression levels. TMEM97 regulates cholesterol trafficking processes such as low density lipoprotein (LDL) uptake by forming complexes with PGRMC1 and low density lipoprotein receptor (LDLR), as well as cholesterol transport out of lysosome by interacting with and regulating NPC1 protein. Understanding molecular functions of TMEM97 in proliferation and cholesterol metabolism will be important to develop strategies to diagnose and treat cancer and cholesterol disorders using a rich collection of TMEM97 radiotracers and ligands.

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 Aβ42, 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 Aβ42 monomers (mAβ42) and oligomers (oAβ42), 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 mAβ42 and oAβ42, 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 mAβ42 and oAβ42 and apoE in primary neurons. Conclusion The TMEM97, PGRMC1, and LDLR complex is a pathway for the cellular uptake of Aβ42 via apoE dependent and independent mechanisms. This study suggests that the complex may potentially be a novel pharmacological target to decrease neuronal Aβ42 internalization and accumulation, which may represent a new strategy for inhibiting the rate of neurotoxicity, neurodegeneration, and progression of AD.