Investigator: Jodi Camberg, University of Rhode Island

Mentor: Nasser Zawia, University of Rhode Island

Scientific Theme: Neuroscience

Abstract: Alzheimer’s Disease (AD) is characterized by the development of amyloid deposits and neurofibrillary tangles in the brain, which interfere with neuronal function and are associated with cognitive decline. These conditions worsen with age as cognitive impairment and dementia progress. Removal or destruction of amyloid plaques has been under investigation as a potential therapeutic treatment option in amyloid- associated, age-related and neurodegenerative diseases such as AD. The functions of molecular chaperone proteins include maintaining the cellular proteome and protecting proteins from aggregation. Some chaperones have been shown to disassemble amyloid fibers in vitro and in vivo by an energy dependent disassembly reaction and others have been suggested to modulate the development of neurofibrillary tangles. To address the complex roles that chaperones play in disease pathogenesis, we will evaluate the expression levels of key ATP-dependent chaperones across several model systems of AD, monitoring both amyloid plaque formation and neurofibrillary tangles. In addition, we plan to engineer a chaperone that partners with a protease to directly target amyloids for destruction. These studies will uncover future potential treatment strategies to reduce aggregate accumulation in AD. Our aims are as follows:
1. Identify and develop molecular chaperone tools to modulate the development of aggregates in AD model systems. We will examine and modulate the expression levels of chaperones (Hsp90 and Hsp70) associated with the development of tau tangles and amyloid plaques in cell culture models of AD to determine if altered expression of Hsp90 or Hsp70 leads to changes in phosphorylated tau or amyloid deposition.
2. Engineer chaperone proteases to disassemble and degrade model amyloids. We will express chaperone proteases (ClpXP and Lon) in a model amyloid system in vivo to determine if either can modulate prion propagation, inheritance and curing. We will engineer mutations in chaperone proteases to enhance amyloid disassembly activity. Chaperones proteases will be investigated in vitro and in vivo to determine if they reduce levels of phosphorylated tau and amyloids.

Human Health Relevance: This project addresses how molecular chaperone proteins can impact the development of toxic aggregates and amyloids in neurodegenerative diseases, such as Alzheimer’s Disease. These studies will shed light on the complex association of chaperone proteins with disease development in widely used model systems of Alzheimer’s Disease and explore novel methods of reducing amyloid burden.