Yang Lab

Head of Lab

Dun-Sheng Yang, PhD

Restoring Defective Waste Recycling in the Brain as a New Therapy for Alzheimer’s Disease

Dr. Yang studies AD pathogenesis in the human brain and in mice at the molecular, cellular, and system levels. The Yang Lab focuses on how neurons degrade and recycle cell constituents via lysosomes—the process termed autophagy (self-eating). Additionally, they investigate the molecular basis for early and progressive corruption of this pathway in AD, which leads to build-up of neurotoxic proteins and ultimately neuronal death. Dr. Yang and his colleagues use AD models and novel transgenic in vivo reporters to evaluate lysosomal failure in the intact brain, which allow his team to validate innovative therapeutic approaches to remediate early failure of the autophagic–lysosomal system in AD.

Current areas of research include:
Manipulating autophagic-lysosomal function of protein degradation in AD mouse models to rescue lysosomal and amyloid pathologies and cognitive deficits.  Extensive autophagic-lysosomal pathology in the AD brain is believed to contribute to AD pathogenesis, but the underlying mechanisms are not well understood.  Our recent studies have revealed that severe lysosomal pathology characterized by enlarged autolysosomes in an AD mouse model is associated with a defect in proteolytic clearance of neuronal autophagic substrates including Aβ, which is considered to account at least in part for the abnormal protein accumulation in the brain.  Genetic enhancement of the autophagic-lysosomal proteolysis substantially ameliorates not only lysosomal pathology along with abnormally accumulated intralysosomal Aβ and ubiquitinated proteins, but also learning and memory deficits, underscoring the potential value of manipulating autophagy as a new strategy for therapeutic intervention in AD.  Currently, other strategies towards restoring or enhancing autophagic-lysosomal proteolysis are under investigation.

Identifying and reversing abnormal lipid storage in AD models. Dysfunction of lipid metabolism has been implicated in AD pathogenesis.  Emerging evidence from AD models suggests abnormal storage of certain lipids associated with autophagic-lysosomal compartments, consistent with the recently identified role of autophagy in intracellular lipid clearance.  Thus, we are interested in identifying autophagy-related lipid impairments in AD models, and particularly, possible interrelationships between abnormal protein and lipid accumulation (outlined in the Box below).  The understanding of these interrelationships will also have relevance to lysosomal storage disorders such as Niemann-Pick type C disease.

Yang

Publications

All publications

Yang lab members


Philip Stavrides, MS - Research Technician