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. 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. 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. 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.