Contactin 5 and Apolipoproteins Interplay in Alzheimer’s Disease

Article type: Research Article

Authors: Dauar, Marina Tedeschi^{a; b; c; d} | Picard, Cynthia^{a; b} | Labonté, Anne^{a; b} | Breitner, John^{a; b; c; e} | Rosa-Neto, Pedro^{c; f; g} | Villeneuve, Sylvia^{a; b; c; e} | Poirier, Judes^{a; b; c; e; *} | for the PREVENT-AD Research Group

Affiliations: [a] Douglas Mental Health University Institute, Montréal, Canada | [b] Centre for the Studies in the Prevention of Alzheimer’s Disease, Montréal, Canada | [c] McGill University, Montreal, Canada | [d] CAPES Foundation, Ministry of Education of Brazil, Brasília, Brazil | [e] Department of Psychiatry, McGill University, Montreal, Canada | [f] Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer’s Disease Research Unit, Douglas Research Institute, Verdun, Canada | [g] Department of Neurology and Neurosurgery, McGill University, Montréal, Canada

Correspondence: [*] Correspondence to: Dr. Judes Poirier, C.Q., Deputy Director, Centre for the Studies in the Prevention of Alzheimer’s disease, Douglas Mental Health University Institute, 6875 Lasalle, Montréal, H4H 1R3, Canada. Tel.: +1 514 761 6131 Ext. 6153, Fax: +1 514 888 4094; Email: judes.poirier@mcgill.ca.

Abstract: Background:Apolipoproteins and contactin 5 are proteins associated with Alzheimer’s disease (AD) pathophysiology. Apolipoproteins act on transport and clearance of cholesterol and phospholipids during synaptic turnover and terminal proliferation. Contactin 5 is a neuronal membrane protein involved in key processes of neurodevelopment. Objective:To investigate the interactions between contactin 5 and apolipoproteins in AD, and the role of these proteins in response to neuronal damage. Methods:Apolipoproteins (measured by Luminex), contactin 5 (measured by Olink’s proximity extension assay), and cholesterol (measured by liquid chromatography mass spectrometry) were assessed in the cerebrospinal fluid (CSF) and plasma of cognitively unimpaired participants (n = 93). Gene expression was measured using polymerase chain reaction in the frontal cortex of autopsied-confirmed AD (n = 57) and control subjects (n = 31) and in the hippocampi of mice following entorhinal cortex lesions. Results: Contactin 5 positively correlated with apolipoproteins B (p = 5.4×10–8), D (p = 1.86×10–4), E (p = 2.92×10–9), J (p = 2.65×10–9), and with cholesterol (p = 0.0096) in the CSF, and with cholesterol (p = 0.02), HDL (p = 0.0143), and LDL (p = 0.0121) in the plasma. Negative correlations were seen between CNTN5, APOB (p = 0.034) and APOE (p = 0.015) mRNA levels in the brains of control subjects. In the mouse model, apoe and apoj gene expression increased during the reinnervation phase (p <  0.05), while apob (p = 0.023) and apod (p = 0.006) increased in the deafferentation stage. Conclusions: Extensive interactions were observed between contactin 5 and apolipoproteins and cholesterol, possibly due to neuronal damage. The alterations in gene expression of apolipoproteins suggest a role in axonal, terminal, and synaptic remodeling in response to entorhinal cortex damage.

Keywords: Alzheimer’s disease, apolipoprotein B, apolipoprotein D, apolipoprotein E, apolipoprotein J, apolipoproteins, CNTN5 , contactin 5, contactins, gene expression

DOI: 10.3233/JAD-231003

Journal: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1361-1375, 2024