The Sigma-2 Receptor/TMEM97, PGRMC1, and LDL Receptor Complex Are Responsible for the Cellular Uptake of Aβ42 and Its Protein Aggregates

Abstract

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.

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Data Availability

Not applicable

Abbreviations

Aβ42:

Amyloid beta 1–42

AD:

Alzheimer’s disease

APP:

Amyloid precursor protein

apoE:

Apolipoprotein E

CNS:

Central nervous system

DKO:

Double knockout

DMPC:

Dimyristoyl-phosphatidylcholine

fAβ42:

Aβ42 fibrils

HFIP:

Hexafluoroisopropanol

LDL:

Low density lipoprotein

LDLR:

Low density lipoprotein receptor

LPDS:

Lipoprotein depleted serum

LRP:

LDLR-related protein

mAβ42:

Aβ42 monomers

oAβ42:

Aβ42 oligomers

PBS:

Phosphate-buffered saline

PBS-T:

Phosphate-buffered saline with 0.2% Tween 20

PGRMC1:

Progesterone receptor membrane component 1

PLL:

Poly L-lysine

TEM:

Transmission electron microscopy

TMEM97:

Transmembrane protein

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Funding

Research was supported by the Michael J Fox Foundation and NIH NIDA T32 Fellowship.

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AR performed and analyzed uptake experiments in HeLa cells and primary rat neurons, ELISA analysis, confocal microscopy experiments, and manuscript preparation. ZL performed and analyzed TEM experiments and Aβ42 fibril preparations, CZ performed CRISPR knockout of HeLa cell lines and Aβ42 microscopy on human tissues, CW performed and analyzed radioligand binding experiments, VL and JT were responsible for tissue sample acquisition, analysis, and pathology, RHM was responsible for experimental organization and rationale, data analysis, organization, and manuscript preparation.

All authors read and approved the final manuscript.

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Correspondence to Robert H. Mach.

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All human tissue was used in accordance with the University of Pennsylvania IRB protocol.

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Riad, A., Lengyel-Zhand, Z., Zeng, C. et al. The Sigma-2 Receptor/TMEM97, PGRMC1, and LDL Receptor Complex Are Responsible for the Cellular Uptake of Aβ42 and Its Protein Aggregates. Mol Neurobiol (2020). https://doi.org/10.1007/s12035-020-01988-1

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Keywords

  • Amyloid beta
  • Alzheimer’s disease
  • Sigma 2 receptor
  • Apolipoproteins
  • Neurons