Mankind has always been challenged by disease. Modern societies have to face a broadvariety of health challenges, some of which are caused by newly emerging pathogens,others become prevalent due to modern westernized lifestyles. One example of healthburdens of our time is Alzheimer’s disease (AD). This neurodegenerative disorder was first described in the early 20th century by Alois Alzheimer. In 2009, the number of Austrians suffering from AD was estimated to be 100.000. As the worldwide prevalence of AD is increasing at an alarming rate, also due to rising life expectancy in modern societies, biomedical research is trying to unveil the underlying molecular mechanisms to allow the development of medical treatment and prevention strategies.
It is established that AD is associated with extracellular deposits of amyloid filaments surrounded by altered neuritic processes and glia, commonly termed “senile plaques”. Previous research has shown that an enzyme called „β-site amyloid precursor protein-cleaving enzyme 1” (BACE1) cleaves the “amyloid precursor protein” (APP) and thereby gives rise to the neurotoxic β-amyloid peptide and, ultimately, the senile plaques (Vassar et al., 1999; Haniu et al., 2000).
Therefore, BACE1 may play a considerable role in the pathogenesis of AD (Wang et al., 2008), making it a promising target in the development of new treatment avenues. However, the molecular mechanisms of BACE1 action and regulation remain elusive.
In 2008, Wang et al. provided evidence for the regulation of BACE1 by the microRNA-107 (miRNA-107). The authors conclude in their study that this form of regulation is crucial for the pathogenesis of AD. Intriguingly, several findings from the literature suggest the existence of multiple transcriptional, translational and posttranslational processes in the regulation of BACE1. In this study, we questioned the role of miRNA-107 in the regulation of BACE1 on the transcriptional level.
Therefore, the overall aim of this project was to elucidate the role of miRNA-107 in the regulation of BACE1 on the mRNA level. To this end we transfected human brain cells (SH-SY5Y) with the precursor miRNA-107 (miRNA-107 mimic). This cell line is a widely used in vitro model in AD research. Upon transfection, miRNA-107 could be processed in the cells and exert its function. We then assessed the mRNA level of BACE1 using quantitative Real-Time PCR (qRT-PCR). The influence of the transfection with miRNA-107 on the BACE1 mRNA level in SH-SY5Y cells compared to untransfected controls should provide new knowledge about the regulation of this key enzyme and therefore shed more light on the molecular mechanisms behind AD.
1.) Haniu M, Denis P, Young Y, Mendiaz EA, Fuller J, Hui JO, Bennett BD, Kahn S, Ross S, Burgess T, Katta V, Rogers G, Vassar R, Citron M (2000) Characterization of Alzheimer’s beta-secretase protein BACE. A pepsin family member with unusual properties. J Biol Chem 275:21099–21106.
2.) Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, et al. (1999) Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286:735–741.
3.) Wang WX, Rajeev BW, Stromberg AJ, Ren N, Tang G, Huang Q, Rigoutsos I, Nelson PT (2008) The expression of microRNA miR-107 decreases early in Alzheimer's disease and may accelerate disease progression through regulation of beta-site amyloid precursor protein-cleaving enzyme 1. The Journal of Neuroscience 28(5):121.
a small protein found in the deposits in the brains of patients with AD
harmful for nerve cells
enzyme that cleaves proteins from the inside
development of a disease and the chain of events leading to it
the process of copying one DNA strand into a complementary RNA (mRNA)
the process by which a protein is made
regulation on the level of the protein