Molecular Regulation of AEP during Ageing

摘要 本提案的目的是表征AEP切割的APP和AEP切割的APP的病理作用。 Tau片段在阿尔茨海默病（AD）发病和进展中的作用以及AEP如何受到分子调控 在老化过程中。AEP是一种酸中毒激活的蛋白酶，对蛋白质的切割具有高度特异性 天冬酰胺残基后的底物。AD的特征是β-淀粉样肽（Aβ）的积累 在脑内沿着有微管相关蛋白Tau的过度磷酸化和切割形式。 内源性AEP受到Cystatin E/M（一种Aβ相关蛋白）的抑制，可预防AD中的神经变性。 最近，我们发现AEP被Aβ激活，并在人类AD大脑中切割APP和Tau， 介导AD病理学。值得注意的是，AEP以年龄依赖性方式在脑和脊髓中表达。我们 发现AEP上调和激活与衰老过程中APP和Tau片段化密切相关。 令人惊讶的是，我们发现C/EBPβ，一个年龄依赖性转录因子，在调节 AEP在衰老过程中的表达。因此，我们推测AEP可能在介导AD中起关键作用 其发病机制由C/EBPβ介导。如能顺利完成拟议的研究， 用于治疗包括AD在内神经退行性疾病的新型药物靶标的鉴定。

Abstract The objectives of this proposal are to characterize the pathological roles of AEP-cleaved APP and AEP-cleaved Tau fragments in Alzheimer's disease (AD) onset and progression and how AEP is molecularly regulated during ageing. AEP is an acidosis-activated protease with a high level of specificity for cleavage of protein substrates after an asparagine residue. AD is characterized by the accumulation of the β-amyloid peptide (Aβ) within the brain along with hyperphosphorylated and cleaved forms of the microtubule-associated protein Tau. Endogenous AEP is inhibited by Cystatin E/M, an Aβ-associated protein, preventing neurodegeneration in AD. Most recently, we show that AEP is activated by Aβ and cleaves APP and Tau in human AD brains and mediates AD pathology. Notably, AEP is expressed in brain and spinal cord in an age-dependent manner. We found that AEP upregulation and activation tightly correlate with APP and Tau fragmentation during ageing. Strikingly, we found that C/EBPβ, an age-dependent transcription factor, plays a critical role in regulating AEP expression during ageing. Hence, we hypothesize that AEP may play a critical role in mediating AD pathogenesis, which is mediated by C/EBPβ. Successful completion of the proposed studies will lead to the identification of a novel drug target for treatment of neurodegenerative diseases including AD.