Relevance of a Truncated PRESENILIN 2 Transcript to Alzheimer’s Disease and Neurodegeneration

Article type: Research Article

Authors: Moussavi Nik, Seyyed Hani^{a; 1} | Porter, Tenielle^{b; c; 1} | Newman, Morgan^a | Bartlett, Benjamin^{c; d; e} | Khan, Imran^c | Sabale, Miheer^{c; f} | Eccles, Melissa^c | Woodfield, Amy^c | Groth, David^c | Dore, Vincent^g | Villemagne, Victor L.^{g; h} | Masters, Colin L.^h | Martins, Ralph N.^{f; i} | Laws, Simon M.^{b; c} | Lardelli, Michael^a | Verdile, Giuseppe^{b; c; *}

Affiliations: [a] University of Adelaide, School of Biological Sciences, Centre for Molecular Pathology, Adelaide, SA, Australia | [b] Collaborative Genomics and Translation Group, Strategic Research Centre for Precision Health, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia | [c] School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, Western Australia, Australia | [d] Department of Advanced Clinical and Translational Cardiovascular Imaging, Harry Perkins Institute of Medical Research, Murdoch, Western Australia, Australia | [e] School of Medicine, University of Western Australia, Crawley, Western Australia, Australia | [f] Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, New South Wales, Australia | [g] Department of Nuclear Medicine and Centre for PET, Austin Health, Heidelberg, VIC, Australia | [h] The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia | [i] School of Medical and Health Sciences, Edith Cowan University, Western Australia, Australia

Correspondence: [*] Correspondence to: A/Prof Giuseppe Verdile, School of Pharmacy and Biomedical Sciences, Curtin University, Bentley, Western Australia, 6102, Australia. Tel.: +61 8 92665618; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Background:The PRESENILIN genes (PSEN1, PSEN2) encoding for their respective proteins have critical roles in many aspects of Alzheimer’s disease (AD) pathogenesis. The PS2V transcript of PSEN2 encodes a truncated protein and is upregulated in AD brains; however, its relevance to AD and disease progression remains to be determined. Objective:Assess transcript levels in postmortem AD and non-AD brain tissue and in lymphocytes collected under the Australian Imaging Biomarker and Lifestyle (AIBL) study. Methods:Full length PSEN2 and PS2V transcript levels were assessed by quantitative digital PCR in postmortem brain tissue (frontal cortex and hippocampus) from control, AD, frontotemporal dementia (FTD), and Lewy body dementia (LBD). Transcript levels were also assessed in lymphocytes obtained from the Perth subset of the AIBL study (n = 160). Linear regression analysis was used to assess correlations between transcript copy number and brain volume and neocortical amyloid load. Results:PS2V levels increased in AD postmortem brain but PS2V was also present at significant levels in FTD and LBD brains. PS2V transcript was detected in lymphocytes and PS2V/PSEN2 ratios were increased in mild cognitive impairment (p = 0.024) and AD (p = 0.019) groups compared to control group. Increased ratios were significantly correlated with hippocampal volumes only (n = 62, β= –0.269, p = 0.03). Conclusion:Taken together, these results suggest that PS2V may be a marker of overall neurodegeneration.

Keywords: Alzheimer’s disease, frontotemporal dementia, Lewy body dementia, lymphocytes, neurodegeneration, Presenilin 2

DOI: 10.3233/JAD-201133

Journal: Journal of Alzheimer's Disease, vol. 80, no. 4, pp. 1479-1489, 2021