Neurodegeneration Research Lab
Therapies for neurodegenerative diseases have failed to improve symptoms or modify disease progression, mainly because of our limited understanding of disease pathogenesis. To advance the field, we need human-based knowledge that provide solid frameworks for mechanistic and functional studies, and improved model systems that account for the high diversity of cell types in the brain and their complex spatial relationships.
Ongoing projects in our lab include:
1. Resolving selective vulnerability and disease progression in human AD brain at the single-cell level. Selective vulnerability, the phenomenon in which specific cell subpopulations are susceptible to pathological insults that lead to cell dysfunction and eventually cell death, is a long-standing question in the field of neurodegeneration. To identify the precise identity of the vulnerable or resistant cell subpopulations and the molecular mechanisms underlying selective vulnerability in AD, we apply single-cell multiomics to archived frozen brain.
2. Investigating mechanisms of tau-related neurodegeneration in human AD brain. In AD, aggregation of hyperphosphorylated tau in neurofibrillary tangles is closely linked to early memory loss and the progression of cognitive deficits. Tau aggregation may contribute to disease progression via early axonal transport defects, synapse dysfunction, and neuroinflammation. However, the cellular and molecular alterations associated with pathological tau in the human brain remain unclear. To unravel the heterogeneity of cellular and transcriptional responses associated with tau pathology, we apply single-cell RNA- and ATAC-seq to single tau-bearing and tau-free neurons isolated from archived frozen brain, and spatial multiomics to map proteomic and transcriptomic changes in the Aβ plaque and NFT microenvironment.
3. Deciphering shared and disease-specific pathways in neurodegeneration. Neurodegenerative disorders show overlapping and distinctive features with regard to the affected brain regions, cell types, and protein aggregates. This complexity is poorly captured by current cellular and animal models. We address these challenges by applying innovative technology to human brain tissue. By comparing the transcriptomes of single cells from patients with Alzheimer’s disease, primary age-related tauopathy, primary tauopathies, and Lewy body disease, we define the shared molecular signatures of neurodegeneration and the disease-specific changes.
4. Multidimensional mapping of vulnerable cell types in humanized Alzheimer's disease mouse models. Although mouse models of AD may not recapitulate the full spectrum of human disease, they remain essential, particularly for studies of the blood-brain barrier, in vivo electrophysiology, behavior, and cell transplantation. We use newly developed knock-in mouse models of AD expressing humanized Ab and human MAPT, with or without dementia-associated mutations, to decipher cell type-specific vulnerabilities and cell-cell interactions in relation to proteinopathies over time. We integrate mouse and human data to identify the cell-type specific behaviors that are evolutionarily conserved or species-specific and evaluate the relevance of our findings to the human condition.
5. Interneuron dysfunction in AD. Impaired inhibitory function has been suggested as a key mechanism of AD-related network dysfunction in humans and mice. Moreover, our single-cell data from the human AD brain shows transcriptional changes in specific cortical interneuron subtypes that begin at very early stages of disease progression. We combine multiomics, transplantation and functional studies in humanized AD mouse models and human AD tissue to characterize the role of interneurons in early protein aggregation, homeostasis, and network dysfunction in AD.