PSA-NCAM Regulatory Gene Expression Changes in the Alzheimer’s Disease Entorhinal Cortex Revealed with Multiplexed in situ Hybridization

Article type: Research Article

Authors: Highet, Blake^a | Wiseman, James A.^a | Mein, Hannah^b | Parker, Remai^a | Ryan, Brigid^a | Turner, Clinton P.^{a; c} | Jing, Yu^b | Singh-Bains, Malvindar K.^a | Liu, Ping^b | Dragunow, Mike^d | Faull, Richard L.M.^a | Murray, Helen C.^{a; 1; *} | Curtis, Maurice A.^{a; 1; *}

Affiliations: [a] Department of Anatomy and Medical Imaging and Centre for Brain Research, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, Auckland, New Zealand | [b] Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand | [c] Department of Anatomical Pathology, LabPlus, Auckland City Hospital, New Zealand | [d] Department of Pharmacology and Centre for Brain Research, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, Auckland, New Zealand

Correspondence: [*] Correspondence to: Maurice A. Curtis, 85 Park Road, Grafton, Private Bag 92019, Auckland 1142, New Zealand. E-mail: [email protected]. and Helen C. Murray, 85 Park Road, Grafton, Private Bag 92019, Auckland 1142, New Zealand. E-mail: [email protected].

Note: [1] Equal supervision of this work and are both regarded as corresponding authors.

Abstract: Background:Alzheimer’s disease (AD) is the most common form of dementia and is characterized by a substantial reduction of neuroplasticity. Our previous work demonstrated that neurons involved in memory function may lose plasticity because of decreased protein levels of polysialylated neural cell adhesion molecule (PSA-NCAM) in the entorhinal cortex (EC) of the human AD brain, but the cause of this decrease is unclear. Objective:To investigate genes involved in PSA-NCAM regulation which may underlie its decrease in the AD EC. Methods:We subjected neurologically normal and AD human EC sections to multiplexed fluorescent in situ hybridization and immunohistochemistry to investigate genes involved in PSA-NCAM regulation. Gene expression changes were sought to be validated in both human tissue and a mouse model of AD. Results:In the AD EC, a cell population expressing a high level of CALB2 mRNA and a cell population expressing a high level of PST mRNA were both decreased. CALB2 mRNA and protein were not decreased globally, indicating that the decrease in CALB2 was specific to a sub-population of cells. A significant decrease in PST mRNA expression was observed with single-plex in situ hybridization in middle temporal gyrus tissue microarray cores from AD patients, which negatively correlated with tau pathology, hinting at global loss in PST expression across the AD brain. No significant differences in PSA-NCAM or PST protein expression were observed in the MAPT P301S mouse brain at 9 months of age. Conclusion:We conclude that PSA-NCAM dysregulation may cause subsequent loss of structural plasticity in AD, and this may result from a loss of PST mRNA expression. Due PSTs involvement in structural plasticity, intervention for AD may be possible by targeting this disrupted plasticity pathway.

Keywords: Alzheimer’s disease, calretinin, entorhinal cortex, polysialyltransferase, PSA-NCAM

DOI: 10.3233/JAD-220986

Journal: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 371-390, 2023