UBC Theses and Dissertations
Ubiquitin carboxyl-terminal hydrolase l1 in alzheimer's disease Zhang, Mingming
Alzheimer’s disease (AD) is the most common form of neurodegenerative diseases. Its neuropathology is characterized by extracellular amyloid plaque deposition, intracellular neuritic fibrillary tangles and neuronal loss. The extracellular amyloid plaque consists of amyloid β (Aβ) protein, which is derived from β- and γ- cleavage of amyloid precursor protein (APP). The abnormal accumulation of Aβ initiates neuronal dysfunction and plays an important role in AD pathogenesis. Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is a de-ubiquitinating enzyme that cleaves ubiquitin at its carboxyl terminal. Dysfunction of UCHL1 has been implicated in various neurodegenerative diseases including childhood-onset progressive neurodegeneration, Alzheimer’s disease and Parkinson’s disease. UCHL1 protein level is reduced in AD and is inversely proportional to the number of neurofibrillary tangles in AD brains.Overexpression of UCHL1 could rescue learning and memory deficits in AD mouse model. However, whether UCHL1 affects APP processing, Aβ production or AD pathogenesis remains unknown. This thesis entails a thorough examination of the role of UCHL1 in AD pathogenesis. First, UCHL1 gene transcriptional regulation was investigated. We identified a functional NF-κB binding site within its 5’promoter region. We found that NF-κB signaling down-regulated UCHL1 transcription. Next we demonstrated that UCHL1 affected APP processing and Aβ production by facilitating the degradation of APP, the precursor of Aβ, and BACE1, the β-secretase in vivo. The results were verified by transgene expression and pharmacological inhibition of UCHL1 in multiple cell lines. Moreover, we showed in neuroblastoma cell lines and primary neuronal culture that UCHL1 protected against oxidative stress- and Aβ-induced neuronal apoptosis by interfering with the caspase 8/caspase 3 pathway. Finally, we demonstrated that UCHL1 reduced Aβ production, inhibited amyloid plaque formation and rescued memory deficits in AD mouse models. In summary, this study investigated the effect of UCHL1 on AD pathogenesis. It demonstrated for the first time that UCHL1 delays the development of AD pathology by regulating APP processing and reducing Aβ production. Furthermore, our findings indicated that transgene expression of UCHL1 is a disease-modifying strategy for AD therapeutic design.
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