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Article

ADAM10 Gene Variants in AD Patients and Their Relationship to CSF Protein Levels

by
Pablo Agüero-Rabes
1,
Julián Pérez-Pérez
2,
Lucía Cremades-Jimeno
3,
María-Salud García-Ayllón
4,5,6,
Adriana Gea-González
4,6,
María José Sainz
1,
Ignacio Mahillo-Fernández
7,
Raquel Téllez
3,
Blanca Cárdaba
3,8,
Javier Sáez-Valero
4,5,9 and
Estrella Gómez-Tortosa
1,*
1
Department of Neurology, Fundación Jiménez Díaz, 28040 Madrid, Spain
2
Secugen S.L., 28040 Madrid, Spain
3
Department of Immunology, IIS-Fundación Jiménez Díaz-UAM, 28040 Madrid, Spain
4
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, 03550 Alicante, Spain
5
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 03550 Alicante, Spain
6
Unidad de Investigación, Hospital General Universitario de Elche, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO), 46020 Valencia, Spain
7
Department of Epidemiology and Biostatistics, Fundación Jiménez Díaz, 28040 Madrid, Spain
8
Centro de Investigación Biomédica en Red Sobre Enfermedades Respiratorias (CIBERES), 28029 Madrid, Spain
9
Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), 03010 Alicante, Spain
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2023, 24(7), 6113; https://doi.org/10.3390/ijms24076113
Submission received: 14 February 2023 / Revised: 13 March 2023 / Accepted: 21 March 2023 / Published: 24 March 2023
(This article belongs to the Special Issue Advances in the Research of Alzheimer's Disease: From Molecular Basis to Therapy)
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Abstract

ADAM10 is the main α-secretase acting in the non-amyloidogenic processing of APP. We hypothesized that certain rare ADAM10 variants could increase the risk for AD by conferring the age-related downregulation of α-secretase. The ADAM10 gene was sequenced in 103 AD cases (82% familial) and 96 cognitively preserved nonagenarians. We examined rare variants (MAF < 0.01) and determined their potential association in the AD group with lower CSF protein levels, as analyzed by means of ELISA, and Western blot (species of 50 kDa, 55 kDa, and 80 kDa). Rare variants were found in 15.5% of AD cases (23% early-onset, 8% late-onset) and in 12.5% of nonagenarians, and some were group-specific. All were intronic variants except Q170H, found in three AD cases and one nonagenarian. The 3′UTR rs74016945 (MAF = 0.01) was found in 6% of the nonagenarians (OR 0.146, p = 0.057). Altogether, ADAM10 total levels or specific species were not significantly different when comparing AD with controls or carriers of rare variants versus non-carriers (except a Q170H carrier exhibiting low levels of all species), and did not differ according to the age at onset or APOE genotype. We conclude that ADAM10 exonic variants are uncommon in AD cases, and the presence of rare intronic variants (more frequent in early-onset cases) is not associated with decreased protein levels in CSF.
Keywords: Alzheimer’s disease; ADAM10; α-secretase; disintegrin metalloproteinase 10 protein; genetics; CSF biomarkers Alzheimer’s disease; ADAM10; α-secretase; disintegrin metalloproteinase 10 protein; genetics; CSF biomarkers

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MDPI and ACS Style

Agüero-Rabes, P.; Pérez-Pérez, J.; Cremades-Jimeno, L.; García-Ayllón, M.-S.; Gea-González, A.; Sainz, M.J.; Mahillo-Fernández, I.; Téllez, R.; Cárdaba, B.; Sáez-Valero, J.; et al. ADAM10 Gene Variants in AD Patients and Their Relationship to CSF Protein Levels. Int. J. Mol. Sci. 2023, 24, 6113. https://doi.org/10.3390/ijms24076113

AMA Style

Agüero-Rabes P, Pérez-Pérez J, Cremades-Jimeno L, García-Ayllón M-S, Gea-González A, Sainz MJ, Mahillo-Fernández I, Téllez R, Cárdaba B, Sáez-Valero J, et al. ADAM10 Gene Variants in AD Patients and Their Relationship to CSF Protein Levels. International Journal of Molecular Sciences. 2023; 24(7):6113. https://doi.org/10.3390/ijms24076113

Chicago/Turabian Style

Agüero-Rabes, Pablo, Julián Pérez-Pérez, Lucía Cremades-Jimeno, María-Salud García-Ayllón, Adriana Gea-González, María José Sainz, Ignacio Mahillo-Fernández, Raquel Téllez, Blanca Cárdaba, Javier Sáez-Valero, and et al. 2023. "ADAM10 Gene Variants in AD Patients and Their Relationship to CSF Protein Levels" International Journal of Molecular Sciences 24, no. 7: 6113. https://doi.org/10.3390/ijms24076113

APA Style

Agüero-Rabes, P., Pérez-Pérez, J., Cremades-Jimeno, L., García-Ayllón, M.-S., Gea-González, A., Sainz, M. J., Mahillo-Fernández, I., Téllez, R., Cárdaba, B., Sáez-Valero, J., & Gómez-Tortosa, E. (2023). ADAM10 Gene Variants in AD Patients and Their Relationship to CSF Protein Levels. International Journal of Molecular Sciences, 24(7), 6113. https://doi.org/10.3390/ijms24076113

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