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Structural biology of cell surface receptors implicated in Alzheimer’s disease

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Abstract

Alzheimer’s disease is a common and devastating age-related disease with no effective disease-modifying treatments. Human genetics has implicated a wide range of cell surface receptors as playing a role in the disease, many of which are involved in the production or clearance of neurotoxins in the brain. Amyloid precursor protein, a membrane-bound signaling molecule, is at the very heart of the disease: hereditary mutations in its gene are associated with a greatly increased risk of getting the disease. A proteolytic breakdown product of amyloid precursor protein, the neurotoxic Aβ peptide, has been the target for many drug discovery efforts. Antibodies have been designed to target Aβ production with some success, although they have not proved efficacious in clinical trials with regards to cognitive benefits to date. Many of the recently identified genes associated with late-onset Alzheimer’s disease risk are integral to the innate immune system. Some of these genes code for microglial proteins, such as the strongest genetic risk factor for the disease, namely APOE, and the cell surface receptors CD33 and TREM2 which are involved in clearance of the Aβ peptide from the brain. In this review, we show how structural biology has provided key insights into the normal functioning of these cell surface receptors and provided a framework for developing novel treatments to combat Alzheimer’s disease.

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Abbreviations

Aβ:

Amyloid-beta

AD:

Alzheimer’s disease

APOE:

Apolipoprotein E

APP:

Amyloid precursor protein

BACE:

β-secretase

CD33:

Myeloid cell surface antigen cluster of differentiation 33

CuBD:

Copper-binding domain

CNS:

Central nervous system

DAP12:

DNAX-activation protein 12

FDA:

U. S. Food and Drug Administration

GFD:

Growth factor–like domain

GWAS:

Genome-wide association studies

HDL:

High-density lipoprotein

HSPG:

Heparin sulfate proteoglycan

Ig:

Immunoglobulin

ITAM:

Immunoreceptor tyrosine–based activation motif

ITIM:

Immunoreceptor tyrosine–based inhibitory motif

JM:

Juxtamembrane

LDL:

Low-density lipoprotein

LDLR:

LDL receptor

LOAD:

Late-onset Alzheimer’s disease

mAb:

Monoclonal antibody

NMR:

Nuclear magnetic resonance

PDB:

Protein databank

PLCG2:

1-Phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2

RMSD:

Root-mean-square-deviation

scFv:

Single-chain variable fragment

siglec:

Sialic acid–binding immunoglobulin (Ig)–like lectin

sTREM2:

Soluble form of TREM2

TREM2:

Triggering receptor expressed on myeloid cells 2

TM:

Transmembrane

VLDL:

Very-low-density lipoprotein

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Acknowledgements

We thank all past and present members of our laboratory, and our collaborators, for their contributions to some of the studies described in this review. This work was supported by the National Health and Medical Research Council of Australia (NHMRC) Project (APP981170, APP156701, APP296201, APP1021935, APP1103026), Research Fellowship (APP1021645, APP1117183) and Investigator (APP1194263) grants, the Alzheimer’s Drug Discovery Foundation, the Angior Family Foundation, Bethlehem Griffiths Research Foundation, the L.E.W. Carty Charitable Fund, the Mason Foundation, the National Foundation for Medical Research and Innovation, and the Yulgilbar Foundation. Infrastructure support from the NHMRC Independent Research Institutes Infrastructure Support Scheme and the Victorian State Government Operational Infrastructure Support Program to St. Vincent’s Institute is gratefully acknowledged. M.W.P. is an NHMRC Leadership Fellow.

Funding

This study was financially supported by the National Health and Medical Research Council (NHMRC) of Australia Investigator Grant (APP1194263, 2021–2025) and the National Foundation for Medical Research and Innovation Research Grant (2021–2022).

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All authors contributed to the preparation of the manuscript and approved the final version.

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Correspondence to Michael W. Parker.

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Conflict of interest

We have a collaboration and license agreement with Janssen Pharmaceuticals on some of our microglia work. Dr Chen Gao is now an employee of Wren Therapeutics Ltd.

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Stefan J. Hermans, Tracy L. Nero, Craig J. Morton, and Jonathan H. Gooi are joint first authors.

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Hermans, S.J., Nero, T.L., Morton, C.J. et al. Structural biology of cell surface receptors implicated in Alzheimer’s disease. Biophys Rev 14, 233–255 (2022). https://doi.org/10.1007/s12551-021-00903-9

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