Doctor of Philosophy (Ph.D.)
Degree Granting Department
Laura Blair, Ph.D.
Robert Deschenes, Ph.D.
Yu Chen, Ph.D.
Daniel Lee, Ph.D.
Vladimir Uversky, Ph.D., D.Sc.
Alzheimer's disease, Amyloid, Dissagregation, Neurodegeneration, Tau
The negative health and economic impacts of neurodegenerative diseases on Americans is astounding and accelerating with an aging population. The Alzheimer’s Association reports that 5.7 million Americans suffer from Alzheimer’s disease (AD), a number which is expected to increase to 14 million by 2050. In economic terms, AD and other neurodegenerative disorders will cost the US over $275 billion in 2018, rising to over $1 trillion annually by 2050. AD causes gross brain atrophy and is most damaging throughout the cortex and the hippocampus, regions required for higher cognitive function and memory. AD presents as tangles within neurons composed of the tau protein, and plaques outside of neurons consisting of amyloid beta. Aggregates have been clearly shown to have associated toxicity.
The past three decades of drug development targeting amyloid beta, an aggregating protein responsible for plaques seen in AD, has failed and currently we have no treatments beyond ameliorative options. Therapeutic alternatives with novel targets are desperately needed in our fight against AD. Therefore, the ultimate goal of this research is to identify novel enzymes involved in aggregation and provide a potential therapeutic option for neurodegeneration capable of lessening tau tangle burden, protecting against the loss of neurons, and preventing cognitive decline.
In AD, both amyloid beta and tau proteins aberrantly aggregate and promote neuronal loss, gross brain tissue degeneration, and cognitive decline. Although the interplay between these two proteins is not well understood, it is clear that targeting amyloid beta has not worked thus far despite over 100 phase III clinical trials targeting amyloid beta. Additionally, it has been repeatedly shown that tau neurofibrillary tangles are correlated with disease severity and not amyloid beta plaques. Finally, tau tangles are present in many other neurodegenerative dementia disorders termed tauopathies including progressive supranuclear palsy, corticobasal degeneration, Pick’s disease, and frontotemporal lobar dementia. Strategies that target tau have a higher chance of success over amyloid beta, and if a therapeutic is found will have a broad impact as tau is involved in so many other devastating neurodegenerative diseases.
Here we show that a human peptidyl prolyl-isomerase (PPIase), cyclophilin 40 (CyP40), dissolves fibrillized tau amyloid fibril in recombinant protein assays, in a human cell model, and in a mouse brain overexpressing human tau. PPIases play an important role in normal cell physiology as catalysts of protein folding at structurally important proline residues for both newly synthesized proteins and in conformational changes for molecular switches. Intrinsically disordered amyloid-forming proteins like tau have proline-rich regions which may regulate aggregation propensity. Our work reveals human CyP40 protein, on its own, possesses remarkable disaggregase activity towards amyloidogenic tau and α-synuclein through interaction with proline residues. CyP40 disaggregase activity is ATP-independent, using its peptidyl-prolyl isomerase activity and untangles amyloid fibrils in vitro. Additionally, CyP40 decreases both tau fibril and oligomer accumulation in a transgenic mouse tauopathy model and delivery of CyP40 to neurons early in the pathogenic progression of the mouse model results in significant improvements in learning and memory as assessed by radial arm water maze and fear conditioning paradigms. This demonstrates a novel human amyloid disaggregation mechanism for CyP40 in addition to its role in maintaining the cellular proteome, and a putative therapeutic target for neurodegenerative disease.
Scholar Commons Citation
Baker, Jeremy Dustin, "Cyclophilin 40 as a Novel Disaggregase" (2018). Graduate Theses and Dissertations.