Upregulated Blood miR-150-5p in Alzheimer’s Disease Dementia Is Associated with Cognition, Cerebrospinal Fluid Amyloid-β, and Cerebral Atrophy

Article type: Research Article

Authors: Chia, Sook Yoong^{a; 1} | Vipin, Ashwati^{b; c; 1} | Ng, Kok Pin^{b; c; d} | Tu, Haitao^a | Bommakanti, Ananth^e | Wang, Brian Zhiyang^b | Tan, Yi Jayne^b | Zailan, Fatin Zahra^{b; c} | Ng, Adeline Su Lyn^{b; d} | Ling, Shuo-Chien^{f; g} | Okamura, Katsutomo^{e; h} | Tan, Eng-King^{g; i} | Kandiah, Nagaendran^{b; c; d; *} | Zeng, Li^{a; c; g; *}

Affiliations: [a] Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, Singapore | [b] Department of Neurology, National Neuroscience Institute, Singapore | [c] Lee Kong Chian School of Medicine, Nanyang Technology University, Novena Campus, Singapore | [d] Duke-NUS Medical School, Singapore | [e] Temasek Life Sciences Laboratory, 1 Research Link National University of Singapore, Singapore | [f] Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore | [g] Neuroscience & Behavioral Disorders Program, Duke-NUS Medical School, Singapore | [h] Nara Institute of Science and Technology, Takayama, Ikoma, Nara, Japan | [i] Research Department, National Neuroscience Institute, Singapore General Hospital Campus, Singapore

Correspondence: [*] Correspondence to: Associate Prof. and Director Nagaendran Kandiah, LKC School of Medicine, Nanyang Technology University, Novena Campus, 11 Mandalay Road, 808232, Singapore. Tel.: +65 6592 2653; E-mail: nagaendran [email protected].; Associate Prof. Li Zeng, Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, Level 6-34, 11 Jalan Tan Tock Seng, 308433, Singapor. Tel.: +65 6357 7515; E-mail: [email protected].

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

Abstract: Background:There is an urgent need for noninvasive, cost-effective biomarkers for Alzheimer’s disease (AD), such as blood-based biomarkers. They will not only support the clinical diagnosis of dementia but also allow for timely pharmacological and nonpharmacological interventions and evaluations. Objective:To identify and validate a novel blood-based microRNA biomarker for dementia of the Alzheimer’s type (DAT). Methods:We conducted microRNA sequencing using peripheral blood mononuclear cells isolated from a discovery cohort and validated the identified miRNAs in an independent cohort and AD postmortem tissues. miRNA correlations with AD pathology and AD clinical-radiological imaging were conducted. We also performed bioinformatics and cell-based assay to identify miRNA target genes. Results:We found that miR-150-5p expression was significantly upregulated in DAT compared to mild cognitive impairment and healthy subjects. Upregulation of miR-150-5p was observed in AD hippocampus. We further found that higher miR-150-5p levels were correlated with the clinical measures of DAT, including lower global cognitive scores, lower CSF Aβ42, and higher CSF total tau. Interestingly, we observed that higher miR-150-5p levels were associated with MRI brain volumes within the default mode and executive control networks, two key networks implicated in AD. Furthermore, pathway analysis identified the targets of miR-150-5p to be enriched in the Wnt signaling pathway, including programmed cell death 4 (PDCD4). We found that PDCD4 was downregulated in DAT blood and was downregulated by miR-150-5p at both the transcriptional and protein levels Conclusion:Our findings demonstrated that miR-150-5p is a promising clinical blood-based biomarker for DAT

Keywords: Alzheimer’s dementia, biomarker, cerebrospinal fluid, MRI, microRNA

DOI: 10.3233/JAD-220116

Journal: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1567-1584, 2022