Research Lab

Translational neuroscience: Targeting aging in neurodegeneration

My lab studies how aging causes gliovascular dysfunction in the brain, and uses the knowledge to guide the test and development of therapeutics for neurological diseases. An exemplary outcome of our basic research is the identification of glucagon-like peptide-1 receptor (GLP-1R) agonists as potential treatments for aging-associated cerebrovascular diseases, based on counteraction of transcriptomic alterations across gliovascular cells and reduction of blood-brain barrier leakage in the aging mouse brain (Zhao et al., Nature Communications, 2020; Li et al., Communications Biology, 2021). Furthermore, we showed that GLP-1R agonism potently counteracts body-wide aging in the mouse, with potency rivalling the mTOR inhibitor rapamycin, and interestingly via a brain-body axis (Huang & Kwok et al., Cell Metabolism, 2025). Our basic research have led us to collaborate with clinical colleagues and conduct phase II proof-of-concept trials, to test the efficacy of GLP-1R agonists in the treatment of cerebral small vessel disease (cSVD) – a strong manifestation of cerebrovascular aging (GAPP-SVD, NCT05356104, ongoing), and large-vessel occlusion (LVO) stroke (GALLOP, NCT05920889, completed). In the GALLOP trial, we demonstrated that in LVO stroke patients receiving endovascular thrombectomy and but not intravenous thrombolysis, adjuvant semaglutide (another GLP-1RA) treatment significantly improved day-90 post-stroke functional outcome (Wang & Ko et al., Nature Communications, 2025) – a finding that has been further substantiated in a phase III study (GALLOP-2, NCT06788626, Wang, Wang & Ko et al., manuscript in submission). Building upon these foundations, we are conducting more mechanistic studies and developing new experimental therapeutics.

Methods development: Tools for translational and systems neuroscience

Many bottlenecks in brain disorder investigations and clinical diagnostics are due to methodological limitations. 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; Sy et al., eLife, 2026), as well as demonstrating that combining a machine learning-derived neuroimaging measure and plasma biomarker enhances the prediction of syndromal conversion in Alzheimer’s disease (Cai et al., Alzheimer’s & Dementia, 2023). Recently, we (i) have developed a machine learning-empowered image processing pipeline for perfusion analysis of eloquent brain regions that enhances our capability to predict day-90 post-stroke functional outcome after thrombectomy (Li et al., in submission), which can improve post-stroke care planning and we aim to extend to help stroke treatment decision making in the future, and (ii) are working on a multimodal brain imaging and biomarker analysis algorithm for Alzheimer’s dementia biological staging and prognostication, that emphasizes generalizability and ease of use under realistic clinical settings (ongoing). These efforts complement our research on the development and optimization of therapeutics for age-related neurological diseases.

1. Body-wide multi-omic counteraction of aging with GLP-1R agonism.
   Huang J, Kwok AJ, Li JCY, Chiu CLH, Ip BYM, Tung LY, Chan RCH, Chan DCW, Wang Z, Zheng X, Chow HT, Lo MPS, Li Z, Lin N, Wang M, Yan LYC, Wu WKK, Chow HM, Lin WJ, Tang Y, Zhang Y, Song W, Ng BWL, Wong SH, Leung TW, Mok VCT, Ko H.
   Cell Metabolism. 2025 Dec 2;37(12):2362-2380.e8. [Nature Aging highlight: 10.1038/s43587-025-01063-1]
2. Glucagon-like peptide-1 receptor agonist in large vessel occlusion treated by reperfusion therapy – a phase 2 randomized trial.
   Wang H^*, Ko H^*,#, Leung TW^*, Huang J, Sai J, Liang Y, Li H, Zhang J, Cao Q, Zang W, Li Y, Ma SH, Lui WT, Choi J, Chan C, Wong J, Kwok AJ, Ma K, Fan F, Chan A, Ip V, Leung H, Soo Y, Wong KT, Lai B, Chu CM, Leung H, Hui AH, Cheung T, Abrigo J, Li SH, Chan L, Yeung J, Pan S, Yip T, Lui LT, Hung T, Tsang SF, Leng XL, Lam B, Mok VCT, Chan RHM, Nguyen T, Hu W, Che F^#, Ip BY^#.
   Nature Communications. 2025 Dec 14; doi:10.1038/s41467-025-66167-z.
3. Comparing machine learning‐derived MRI‐based and blood‐based neurodegeneration biomarkers in predicting syndromal conversion in early AD.
   Cai Y, Fan X, Zhao L, Liu W, Luo Y, Lau AYL, Au LCW, Shi L, Lam BYK, Ko H^#, Mok VCT.
   Alzheimer’s & Dementia. 2023 Nov;19(11):4987-4998.
4. 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.
5. 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.
6. 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.
7. Refinement of learned skilled movement representation in motor cortex deep output layer.
   Li Q*, Ko H*, Qian ZM, Yan LYC, Chan DCW, Arbuthnott GW, Ke Y, Yung WH.
   Nature Communications. 2017 Jun 9;8:15834.
8. The emergence of functional microcircuits in visual cortex.
   Ko H, Cossell L, Baragli C, Antolik J, Clopath C, Hofer SB, Mrsic-Flogel TD.
   Nature. 2013 Apr 4;496(7443):96-100.
9. Differential connectivity and response dynamics of excitatory and inhibitory neurons in visual cortex.
   Hofer SB*, Ko H*, Pichler B, Vogelstein J, Ros H, Zeng H, Lein E, Lesica NA, Mrsic-Flogel TD.
   Nature Neuroscience. 2011 Jul 17;14(8):1045-52.
10. Functional specificity of local synaptic connections in neocortical networks.
    Ko H, Hofer SB, Pichler B, Buchanan KA, Sjöström PJ, Mrsic-Flogel TD.
    Nature. 2011 May 5;473(7345):87-91.