Our research focuses on how aging leads to pathological protein aggregation and neuronal vulnerability using wild-type or AD mouse models and primary neurons in culture that provide mechanistic insights.

A particular type of tau accumulates in the brains of wild-type mice as a consequence of normal aging.

Investigate the evolution of tau during lifespan

Hyperphosphorylated tau represents one of the hallmark pathologies observed in aged and AD patients. However, the status of tau during normal aging in the absence of overt neurodegeneration is poorly understood. We demonstrated that a particular type of tau accumulates in the hippocampus of wild-type mice during normal aging. However, the comprehensive signature of tau in different life stages, and how tau changes over time remains unknown. We are trying to decipher the conversion of tau during an animal’s lifespan and understand its biological implication.

Potential tau interaction partners in mitochondria (left panel) and synapse (right panel) from Tracy et al 2022.

Understand the non-traditional roles of tau in the brain and their implication in aging and AD

Tau has been traditionally considered solely as a microtubule regulator in the brain. However, recent studies shed light on tau’s role in modulating diverse neuronal functions including axonal transport, mitochondrial function, synaptic integrity, and neurotrophic pathways. Here we try to unravel the detailed mechanisms by which tau influences these essential neuronal functions and therefore highlight potential therapeutic targets to block tau-mediated toxicity.

By employing proteomics approaches, we are hoping to understand how age-related triggers lead to neuronal vulnerability.

Dissect the mechanisms by which age-related perturbations impact neuronal vulnerability

Increased levels of reactive oxygen species, neuroinflammation, and DNA damage are firmly implicated in aging and AD, and are often employed as age-related triggers in disease models. Our previous work has shown that oxidative stress leads to an altered global proteomic profile and induces insoluble protein aggregation in neurons. By LC-MS/MS, we identified more than 600 targets in the cytoplasm that are abnormally modified in response to oxidative stress. These modified targets are tightly linked to critical neuronal functions including cytoskeletal dynamics and synaptic integrity. We are hoping to understand how these aberrantly modified proteins lead to neuronal vulnerability.

Techniques utilized in the Tseng Lab