Neural Stem Cell Research Laboratory

ZENG Li, Ph.D.

Principal Investigator, Research, National Neuroscience Institute (NNI)
Deputy Director, Basic Science & Translational Research, NNI
Associate Professor, Neuroscience and Behavioral Disorders Programme, Duke-NUS Medical School
Adjunct Associate Professor, Lee Kong Chian School of Medicine, Nanyang Technological University

Contact Information

Neural Stem Cell Research Laboratory
Research Department
National Neuroscience Institute
11 Jalan Tan Tock Seng, Singapore 308433
Tel: (65) 6357 7515 (Office) / (65) 6357 7505 (Lab)
Email: Li_ZENG@nni.com.sg

The Team

• TU Haitao, Ph.D. (Research Fellow)
• CHI Li, Ph.D. (Visiting Research Fellow)
• HANG Zhi Wei, B.Sc. (Senior Research Officer)
• Sarivin VANAN, B.Sc. (Ph.D. student)
• Jolene LEE Wei Ling, B.Sc. (Ph.D. student)
• CHIA Sook Yoong, B.Sc. (Laboratory Manager)

Overview

Alzheimer’s disease (AD) is the most common neurodegenerative disease seen in Singapore. Recent evidences suggested that impaired neurogenesis might contribute to cognitive dysfunction observed in AD. Amyloid precursor protein (APP) is a type I transmembrane glycoprotein proteolytically processed to release Aβ (amyloid beta), a pathological hallmark of AD. Although, this protein is expressed throughout the developing and mature brain; the roles of APP in neural development and neural stem cell function are not well established. microRNAs (miRNAs) are small non-coding RNA molecules that function in the transcriptional and post-transcriptional regulation of gene expression in a variety of organisms.

The role of miRNAs in neuronal development and neural stem cell function has been recently identified. Notably, dysregulated miRNAs have been implicated in AD. We aim to unravel the molecular mechanisms underlying APP-dependent miRNA-mediated neuronal differentiation in AD; working with clinician doctors at NNI, we aim to develop miRNAs as biomarkers for AD by detecting miRNAs level changes in cerebrospinal fluid (CSF), and peripheral blood mononuclear cells (PBMCs) from AD subjects, compared to the healthy individuals. Our research will advance the understanding of miRNA regulatory pathway in association with impaired neurogenesis and cognitive dysfunction observed in AD. Importantly, our study will identify miRNAs as novel non-invasive diagnostic biomarkers, and help in developing miRNA-based therapeutics strategy in AD.

In addition, we have been collaborating with Professor Tan Eng King, a Clinician Scientist at the Department of Neurology, NNI@SGH, to incorporate genetically modified mice model of PD and neural stem cell/neuron cell cultures into our analysis to identify  potential pathogenic factors, substrates, miRNAs and their regulatory pathways at the molecular, cellular, network, and behavioral level. Mouse models are also being used to develop and evaluate novel treatment strategies. Their relevance is assessed through the comparative studies of humans and postmortem tissues to establish prospective collaboration with clinical programmes.

Recently, in order to circumvent the caveat in recapitulating the complexity and delicacy of the human brain, we generate 3-dimensional model of the human brain through cerebral organoids using human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs).

Our goal is to

1. Elucidate the molecular pathology of NNI dementia patient iPSC-derived cerebral organoids
2. Characterise the differential spatiotemporal cellular expression of molecular markers
3. Identify aberrant neuronal signaling of the diseased lines in hopes to better define cellular hallmarks in early disease progression.

Our study would value-add to the development of drug screening applications and personalised medicine strategy that targets dementia patients in early phase diagnosis.

iPSC-derived human dopaminergic neurons stained with TH (red) and neuronal marker Tuj1 (green) at day 36 after neuronal differentiation.

The image shows staining for markers of autophagy (green) and dopaminergic neurons (red) in brain tissue from LRRK2-mutant mice.

Selected Publications

1. Tu H, Yeo XY, Zhang ZW, Zhou W, Tan JY, Chi L, Chia SY, Li Z, Sim AY, Singh BK, Ma D, Zhou Z, Bonne I, Ling SC, Ng ASL, Jung S, Tan EK, Zeng L. NOTCH2NLC GGC intermediate repeat with serine induces hypermyelination and early Parkinson's disease-like phenotypes in mice. Mol Neurodegener 2024 Nov 28;19(1):91. doi: 10.1186/s13024-024-00780-2.
2. Jiang M, Jang SE, Zeng L. The Effects of Extrinsic and Intrinsic Factors on Neurogenesis. Cells　2023. doi:10.3390/cells12091285
3. Long YH, Ang KS, Li M, Kelvin Chong KL, Sethi R, Zhong C, Xu H, Ong ZW, Sachaphibulkij K, Chen A, Zeng L, Fu H, Wu M, Lina Lim HK, Liu L, Chen J. Spatially informed clustering, integration, and deconvolution of spatial transcriptomics with GraphST. Nature Communication 2023. Doi: 10.1038/s41467-023-36796-3
4. Kumar P, Lim A, Hazirah SN, Chua CJH, Ngoh A, Poh SL, Yeo TH, Lim J, Ling S, Sutamam NB, Petretto E, Low DCY, Zeng L, Tan EK, Arkachaisri T, Yeo JG, Ginhoux F, Chan D, Albani S. Single-cell transcriptomics and surface epitope detection in human brain epileptic lesions identifies pro-inflammatory signaling. Nat Neurosci. 2022 Jul;25(7):956-966.
5. Zhang ZWⴕ, Tu HTⴕ, Jiang M, Vanan S, Chia SY, Jang SE, Saw WT, Ong ZW, Ma DR, Zhou ZD, Xu J, Guo KW, Yu WP, Ling SC, Margolin RA, Chain DG, Zeng L*, Tan EK*. APP Intracellular Domain Promotes Expression of LRRK2 Enabling a Feed-Forward Loop of Neurodegeneration in Parkinson’s Disease. Science Signaling 2022. DOI: 10.1126/scisignal.abk3411. *co-senior authors
6. Chia SYⴕ, Vipin Aⴕ, Ng KP, Tu HT, Bommakanti A, Wang BZ, Tan YJ, Zailan FZ, Ng ASL, Ling SC, Okamura K, Tan EK, Kandiah N*, Zeng L*. Upregulated Blood miR-150-5p in Alzheimer’s Disease Dementia Is Associated with Cognition, Cerebrospinal Fluid Amyloid, and Cerebral Atrophy. Journal of Alzheimer’s Disease 2022. DOI: 10.3233/JAD-220116. *co-senior authors
7. Tu H, Zhang ZW, Qiu L, Lin Y, Jiang M, Chia SY, Wei YF, Ng ASL, Reynolds R, Tan EK, Zeng L. Increased expression of pathological markers in Parkinson’s disease dementia post-mortem brains compared to dementia with Lewy bodies. BMC neuroscience 2022. DOI:10.1186/s12868-021-00687-4
8. Jang SEⴕ, Qiu Lⴕ, Cai X, Lee JWL, Zhang W, Tan EK, Liu Bin, Zeng L. Aggregation-induced Emission (AIE) Nanoparticles Labeled Human Embryonic Stem Cells (hESCs)-derived Neurons for Transplantation. Biomaterials 2021. DOI:10.1016/j.actbio.2018.07.051
9. Jiang M, Tu HT, Zhang K, Zhang W, Yu WP, Xu J, Tan EK, Guo KH, Zeng L. Impaired neurogenesis in the hippocampus of an adult VPS35 mutant mouse model of Parkinson’s disease through interaction with APP. Neurobiology of Disease 2021. DOI: 10.1016/j.nbd.2021.105313
10. Jiang M, Vanan S, Tu HT, Zhang W, Zhang ZW, Chia SY, Jang SE, Zeng XX, Yu WP, Xu J, Guo KH, Zeng L. APP Intracellular Domain (AICD)-dependent regulation of FOXO3a Inhibits Adult Hippocampal Neurogenesis, Neurobiology of Aging 2020. DOI: 10.1016/j.neurobiolaging.2020.07.031.
11. Damodar VR Qiu L, Lee JWL, Chen X, Jang SE, Chai C, Lim, KL, Tan EK, Zhang Y, Huang WM, Zeng L. A microfiber scaffold-based 3D in vitro human neuronal culture model of Alzheimer’s disease. Biomaterials Science 2020. DOI: 10.1039/d0bm00833h.
12. Qiu L., Liao M.C. et al., Zeng L.* & Robins E.G.*. Dopamine transporter neuroimaging accurately assesses the maturation of dopamine neurons in a preclinical model of Parkinson’s disease. Stem Cell Research & Therapy 2020. DOI: 10.1186/s13287-020-01868-4. *co-senior authors
13. Vanan S., Zeng X., Chia S.Y., Varnäs K., Zhang K., Jiang M., Padmanabhan P., Yu W.P., Zhou Z.D., Halldin C., Gulyás B., Tan E.K., Zeng L. Altered striatal dopamine levels in Parkinson’s disease VPS35 D620N mutant transgenic aged mice. Molecular Brain 2020. DOI: 10.1186/s13041-020-00704-3
14. Jang SE, Qiu L, Chan LL, Tan EK and Zeng L.. Current status of stem cell-derived therapies for Parkinson’s disease: From Cell Assessment and Imaging Modalities to Clinical Trials. Frontiers in Neuroscience 2020. 14, 5585324. DOI: 10.3389/fnins.2020.558532
15. Zhang W,　Tan YW,　Yam WK,　Tu H,　Qiu L,　Tan EK,　Chu JJH,　Zeng L. In utero infection of Zika virus leads to abnormal central nervous system development in mice. Sci Rep.　2019. 13;9(1):7298. DOI: 10.1038/s41598-019-43303-6.
16. Chen Z, Zhang W, Chua LL, Chai C, Li R, Lin L, Cao Z, Angeles D. C, Stanton W. L, Peng J, Zhou ZD, Lim KL, Zeng L.* Tan EK*. Phosphorylation of amyloid precursor protein by mutant LRRK2 promotes AICD activity and neurotoxicity in Parkinson’s disease. Sci Signal. 2017. 10(488). pii: eaam6790. DOI: 10.1126/scisignal.aam6790. *co-senior authors.
17. Qiu L, Liao MC, Chen AK, Wei S, Xie S, Reuveny S, Zhou ZD, Hunziker W, Tan EK, Oh SKW, Zeng L. Immature Midbrain Dopaminergic Neurons Derived from Floor-Plate Method Improve Cell Transplantation Therapy Efficacy for Parkinson's Disease. Stem Cells Transl Med. 2017. DOI: 10.1002/sctm.16-0470.
18. Chen Z, Cao Z, Zhang W, Gu M, Zhou ZD, Li B, Li J, Tan EK*, Zeng L.* LRRK2 Interacts with ATM and Regulates Mdm2-p53 Cell Proliferation Axis in Response to Genotoxic Stress. Hum Mol Genet 2017. 26(22):4494-4505. DOI: 10.1093/hmg/ddx337. *co-senior authors
19. Zhang W, Kim PJ, Chen Z, Lokman H, Qiu L, Zhang K, Rozen SG, Tan EK, Je HS, Zeng L. MicroRNA-128 Regulates the Proliferation and Neurogenesis of Neural Precursors by Targeting Pericentriolar Material 1 (PCM1) in the Developing Neocortex. eLlife 2016. 5. pii: e11324. DOI: 10.7554/eLife.11324.
20. Qiu, L., Ng, G., Tan, E.K., Liao, P., Kandiah, N., Zeng, L (2016) Chronic cerebral hypoperfusion enhances Tau hyperphosphorylation and reduces autophagy in Alzheimer’s disease mice. Sci Rep. 6:23964. DOI: 10.1038/srep23964.
21. Zhang, W., Thevapriya, S., Kim, P.J., Yu, W., Je, HS., Tan, E.K., Zeng, L (2014) Amyloid precursor protein regulates neurogenesis by antagonizing miR-574-5p in the developing cerebral cortex. Nat. Commun. 5:3330. DOI: 10.1038/ncomms4330.