Research Lab

Translational neuroscience: targeting aging in neurodegeneration

My team adopts a multimodal approach combining genetic manipulations, molecular assays, in vivo functional and structural imaging to interrogate how aging and neurodegenerative disease-related genetic mutations cause glial and vascular dysfunction. By understanding the underlying pathogenesis, we are especially interested in using the knowledge to guide the test and development of disease-modifying therapeutics. An exemplary outcome of our basic science research is the identification of glucagon-like peptide-1 receptor (GLP-1R) agonists as potential treatments to modify the disease course of age-related vasculopathy (Zhao et al., Nature Communications, 2020 Sep 4;11(1):4413; Li et al., Communications Biology, 2021 Jun 2;4(1)656). This has led us to collaborate with clinical colleagues and initiate an ongoing phase II trial (GAPP-SVD trial, NCT05356104) to test the efficacy of a GLP-1R agonist in the treatment of cerebral small vessel disease (cSVD). Furthermore, our recent laboratory work indicates that GLP-1R agonism is a potent method for mitigating age-related functional and molecular changes throughout the mouse body, rivaling the mTOR inhibitor rapamycin, and interestingly acting via a brain-body axis (Huang et al., BioRxiv, 2024; manuscript in revision). Building upon this foundation, we are conducting further mechanistic studies and developing new experimental therapeutics.

Methods & tools for systems and translational neuroscience

Methodological limitations often create bottlenecks in brain disorder investigations and clinical diagnostics. To address these challenges, our research focuses on developing advanced imaging tools for both preclinical studies and clinical applications. Specifically, we concentrate on two key areas: (i) high-throughput, three-dimensional neuronal activity and molecular profiling in the brain, and (ii) deployable clinical diagnostics that enhance the management of neurological disorders. Notable accomplishments of my team include the development of a method for thermostabilizing antibodies, enabling heat-accelerated deep immunostaining of intact organ tissues (Lai et al., Nature Methods, 2022; Yau et al., Cell Reports Methods, 2023), and an optofluidic system for imaging whole-brain chemosensory neuronal responses (Sy et al., Nature Communications, 2023). Currently, we are further advancing (i) high-throughput brain-wide imaging platforms for studying sensorimotor integration in healthy animals and disease models, (ii) machine learning-enhanced image processing algorithms for brain perfusion analysis to enhance our capability to optimize treatment plan and predict the clinical outcome for stroke patients, and (iii) deep learning-based MRI brain analysis algorithm for Alzheimer’s dementia biological staging. These complement our research on therapeutics for age-related neurovascular and neurodegenerative diseases.

1. Functional and multi-omic aging rejuvenation with GLP-1R agonism. Huang J, Kwok AJ, Li JCY, Chiu CLH, Ip BYM, Tung LY, Zheng X, Chow HT, Lo MPS, Li Z, Chan RCH, Lin N, Wang Z, Wang M, Yan LYC, Chan DCW, Wu WKK, Chow HM, Lin WJ, Tang Y, Ng BWL, Wong SH, Leung TW, Mok VCT, Ko H. bioRxiv. doi: 10.1101/2024.05.06.592653

2. An optofluidic platform for interrogating chemosensory behavior and brainwide neural representation. Sy SKH, Chan DCW, Chan RCH, Lyu J, Li Z, Wong KKY, Choi CHJ, Mok VCT, Lai HM, Randlett O, Hu Y, Ko H. Nature Communications. 2023 Jan 14;14(1):227.

3. Antibody stabilization for thermally accelerated deep immunostaining. Lai HM, Tang Y, Lau ZYH, Campbell RAA, Yau JCN, Chan DCW, Wong HKT, Yan LYC, Wu WKK, Wong SH, Kwok KW, Wing YK, Ng HK, Mrsic-Flogel TD, Mok VCT, Chan JYK, Ko H. Nature Methods. 2022 Sep 1;19(9):1137-1146.

4. Systemic GLP-1R agonist treatment reverses mouse glial and neurovascular cell transcriptomic aging signatures in a genome-wide manner. Li Z, Chen X, Vong JSL, Zhao L, Huang J, Yan LYC, Ip B, Wing YK, Lai HM, Mok VCT, Ko H. Communications Biology. 2021 Jun 2;4(1):656.

5. Pharmacologically reversible zonation-dependent endothelial cell transcriptomic changes with neurodegenerative disease associations in the aged brain. Zhao L, Li Z, Vong JSL, Chen X, Lai HM, Yan LYC, Huang J, Sy SKH, Tian X, Huang Y, Chan HYE, So HC, Ng WL, Tang Y, Lin WJ, Mok VCT, Ko H. Nature Communications. 2020 Sep 4;11(1):4413.