‘Mini-brain’ neurospheres stained to show cell nuclei and amyloid beta deposits (left), oxidative stress state (middle), and imaged using spatial transcriptomics (right).
Alzheimer’s disease at a glance
Alzheimer’s disease is a chronic, progressive neurodegenerative disease characterized by declining memory and cognitive abilities. As the most common form of dementia, it represents a major unmet medical challenge. Although there are some treatments that can help manage symptoms in the early stages of Alzheimer’s disease, there is currently no cure.
A hallmark pathological feature of Alzheimer’s disease is the accumulation of amyloid beta plaques in the brain. These plaques disrupt communication between neurons, leading to neuronal dysfunction and ultimately cell death. However, some patients with significant amyloid beta plaque burden remain cognitively intact and are considered ‘resilient’. Understanding the genetic or cellular mechanisms that underly this resilience and protect neurons from disease-related damage, is the central focus of our research..
Advanced disease modelling with neurospheres
Our research builds on innovative work from the MacVicar and Nygaard laboratories, which established a three-dimensional culture system called neurospheres. These ‘mini-brains’, consist of multiple brain cell types, organized into a three-dimensional culture system, allowing key pathological features of Alzheimer’s disease to be modelled more faithfully than traditional two-dimensional or single cell type culture systems.
Neurospheres enable detailed investigation of amyloid beta plaque development and its effects on neuronal health, cellular interactions, and disease progression. This platform provides a powerful experimental system for identifying early cellular changes that may contribute to vulnerability or resilience in Alzheimer’s disease.
Next-generation transcriptomics and target discovery
Cellular behaviour in health and disease is governed by gene expression, which determines what proteins are produced and how cells respond to their environment and communicate with one another. Understanding both which genes are expressed and where they are expressed within the brain tissue is critical for understanding disease mechanisms.
We apply next-generation transcriptomic approaches – including single cell and single nucleus RNA sequencing and spatial transcriptomics – to achieve high-resolution analysis of gene expression across cell types and tissues. Leveraging transcriptomic platforms at UBC and expertise from the Miller lab, we examine how individual brain cell populations respond to amyloid beta pathology and interact within the neurosphere model.
Translational Impact
By integrating data from neurosphere-based experiments with transcriptomic analyses of patient-derived samples, the Dementia Therapeutics Innovation Initiative aims to identify key differences in cells, genes, proteins, and biological pathways between resilient individuals and patients with Alzheimer’s disease. These insight are expected to reveal novel therapeutic targets and inform the development of future disease-modifying treatments.
Research Projects
Our neurosphere-based research projects involve the differentiation of human induced pluripotent cells (hi-PSCs) into neurons and glial cells, which are cultured as 3D spheres. These spheres can be treated with amyloid beta (Abeta), peptides that are the main component of amyloid plaques in Alzheimer’s disease, to induce an Alzheimer’s-like pathology including changes in oxidative stress that are linked to neuronal cell death. Using this model, we can dissociate the spheres to perform single-nucleus RNA sequencing or section them to perform spatial transcriptomic analysis to examine the cellular and molecular changes that occur in the presence of Abeta and in response to the presence or absence of the brain’s immune cells, microglia. These next-generation analyses will help us to identify novel cellular or molecular targets for Alzheimer’s disease. Once potential targets are identified, this neurosphere model can also be used to perform high-throughput in vitro testing of candidate drugs.
UBC is home to a world-class bio-bank of tissues including brain samples from patients with Alzheimer’s disease. Using these tissues, we can perform single-nucleus RNA sequencing and spatial transcriptomics to identify cellular and molecular changes between resilient and Alzheimer’s disease patients. By comparing targets identified in neurosphere studies with targets identified in patient samples, we can refine these targets to focus on the most promising ones for drug testing and development.
In collaboration with Dr. Xin Tang, the DTII will use machine learning to facilitate target identification and in the future, in silico drug testing. One of our main objectives is to integrate spatial transcriptomic data with oxidative stress and immunofluorescent imaging using machine learning. This will allow us to combine information about gene expression with cell state and protein expression data to identify cellular and molecular targets that are associated with Abeta plaques and neuronal cell death.
Publications
2025
A 3D human iPSC-derived multi-cell type neurosphere system to model cellular responses to chronic amyloidosis
Wendt S, Lin AJ, Ebert SN, Brennan DJ, Cai W, Bai Y, Kong DY, Sorrentino S, Groten CJ, Lee C, Frew J, Choi HB, Karamboulas K, Delhaye M, Mackenzie IR, Kaplan DR, Miller FD, MacVicar BA, Nygaard HB.
J Neuroinflammation. 2025 Apr 24; 22(1):119
Generation of 3D Human iPSC-Derived Multi-Cell Type Neurospheres for Studying Neuron, Astrocyte, and Microglia Crosstalk
Wendt, S., Lee, C., Cai, W., Lin, A. J., Huang, J., Poon, V., Xiang, X., Hong, W., MacVicar, B. A. and Nygaard, H. B.
Bio-protocol. 2025 Nov 5; 15(21): e5493
Geometrical constraints dictate assembly and phenotype of human iPSC-derived motoneuronal spheroids
Eleonora Mello, Stefano Sorrentino, Alessio Bucciarelli, Ermanno Cordelli, Elisa De Luca, Haakon Nygaard, Stefan Wendt, Alberto Rainer, Giuseppe Gigli, Lorenzo Moroni, Alessandro Polini, Pamela Mozetic.
Stem Cell Research & Therapy. 2025 Jul 31; 16 (1): 417
A microglia-containing cerebral organoid model to study early life immune challenges
Alice Buonfiglioli, Raphael Kübler, Roy Missall, Renske De Jong, Stephanie Chan, Verena Haage, Stefan Wendt, Ada J Lin, Daniele Mattei, Mara Graziani, Brooke Latour, Frederieke Gigase, Rebecca Chiu, Ya Zhang, Haakon B Nygaard, Philip L De Jager, Lot D De Witte.
Brain, Behavior, and Immunity. 2025 Jan; (123)
