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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: [email protected]

 

The Team

  • TU Haitao, Ph.D. (Research Fellow)
  • QIU Lifeng, Ph.D. (Research Fellow)
  • CHIA Sook Yoong, B.Sc. (Senior Research Officer and Laboratory Manager)
  • ZHANG Zhi Wei, M. Med. (Senior Research Officer)
  • GAO Shujun, M. Med. (Research Officer)
  • Sarivin VANAN, B.Sc. (Ph.D. student)
  • Jolene LEE Wei Ling, B.Sc. (Ph.D. student)
  • LI Zhihong, M. Sc. (Ph.D. student)

 

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.

Working model: AICD cooperates with the transcription factor FOXO3a to promote LRRK2 transcriptional activation and LRRK2 expression, leading to LRRK2-induced neurodegeneration (Zhang et. al. Sci. Signal. 2022).

A graphical summary illustrates that N2C-polyG intermediate repeat with serine induces neurotoxicity and early PD-like neurodegeneration in vitro and in vivo. (Tu et al., Mol. Neurodegener. 2024).

 

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. *co-senior authors.
  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. Nat. Commun. 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. Sci. Signal. 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. J. Alzheimer. Dis. 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 Neurosci. 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. Neurobio. Dis. 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, Neurobio. 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. Biomater. Sci. 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 Res. Ther. 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. Mol. 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. Front. Neurosci. 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.

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