Neurodegeneration Research Lab

Therapies for neurodegenerative diseases have largely 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 can 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 the 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 are using single-nucleus RNA-seq of archived frozen brain. This method is cost-effective and sensitive, and allows unbiased cell type classification, quantitative gene expression profiling, and characterization of disease-associated cell states. Because AD pathology spreads across cerebral cortical regions in a highly predictable and stereotypical manner (entorhinal _> associative _> primary cortices), we are comparing early- and late-involved regions from the same brain to obtain a pseudotime reconstruction of disease progression. This strategy provides a comprehensive view of the vulnerable and resistant cell types in AD, their transcriptome changes, and the spread of those changes over time and across cortical regions.

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. Thus, studies aimed at understanding the mechanisms of tau-related neurodegeneration could lead to better diagnostic tools and perhaps treatments. Tau hyperphosphorylation contributes to disease progression via early axonal transport defects, synapse dysfunction, and neuroinflammation, whereas mature neurofibrillary tangles appear to have toxic gain-of-function effects. However, our understanding of the cellular and molecular alterations associated with tau aggregates remains limited. We have developed a new assay to isolate and profile tangle-bearing cells from postmortem human brain. By comparing the transcriptomes of single neurons with tangles to those of neighboring tangle-free neurons, we identify the precise neuronal subtypes that are vulnerable to tau pathology and characterize the cell-type-specific and commonly altered genes and pathways associated with tau aggregation.

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 are addressing 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 are beginning to define the shared molecular signatures of neurodegeneration and the disease-specific changes.

4. Comparing the cellular phenotypes of mouse models and human neurodegenerative tauopathies

Although mouse models of AD and related tauopathies do 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. By comparing mouse and human transcriptomes, we are beginning to identify the cell-type specific behaviors that are evolutionarily conserved or species-specific.