Biomarkers for Alzheimer’s Disease Progression

Biomarkers for Alzheimers Disease ProgressionAlzheimers disease is slowly progressive and irreversible wizardry disease which is one of the most common cause of dementia 1. In AD patients not only suffer from cognitive but also motor and sensory(a) loss 2. Although the mechanism of AD is not well understood still AD pathology is characterized by extra cellular amyloid- deposits and interacellular neurfibril tangles formation of hyperphosphorylation of tau protein. Being irreversible and neurologic damaging disease, its very important to detect and diagonse at earlier or at some controlable time point. Some useful AD diagonstic biomarkers are necessitate for this purpose. These biomarkers should also fullful the criteria of usefulness for AD detection. Biomarkers should become abnormal with the progression of disease in other words they should be dynamic and correlate with clinical presage and severity of disease 3.Recent research on use of specific AD biomarker for disease stagi ng in vivo shows that A dynamically correlates with disease at different stages of disease progression4 5. But A level varies in patients. Which suggests, with process of A production starts earlier but A as a biomarker only is not relibale, therefore alternative biomarker must be found along with A generation process.Figure1. Biomakers and AD early detectionSource circumscribed from Ingelsson, M et al 2004. 4A can be produced through proteolytic touch on of APP (amyloid precursor protein), which takes central position in AD pathogenesis. APP is single-pass transmembrane protein with larger ectodomain. Although the physiologic functions of APP are not well known but has neuroprotective function and positive effect on cell growth 6.APP is mainly produced in neurons and rapidly metabolized by secretase enzymes through alternative splicing by 2 pathways 7 8. Nonamyloidogenic processing of APP involving two secretases -secretase and -secretase while in amyloidogenic processing -secr etase (identified as transmembrane aspartase protease BACE1) and -secretase are involved. Product generated during some(prenominal) processings have soluble ectodomain (sAPP and sAPP ) respectively along with identical product called AICD (intracellular C-terminal fregmenets)9. More importantly amyloidogenic processing generates A, a sequence contained by sAPP part. In brain APP processing generates mainly A40 and A42 based on 40 and 42 amino acids residues depending on secretases ( see secretase table 1) through alternative splicings 10. Along with regulatory subunits of -secretase complex, catalytic subunits presenilin1 (PS1) and presenilin 2 ( PS2) are involved mainly in deciding the length of these venomous form of A. These toxic forms of A can aggregate and form plauqe that has more toxic effect 11.With the progression of AD, symptoms also spread along with it depending on the vlunerability of different party of noisome system. More vlunerable areas are suppose to be effec ted earlier to others, the reason AD smptoms appear in different regions in a sequential tack and consistency, although meachnism is poorly understood. Out of these early symtoms, one is olfactory impairement 12, which suggest olfactory system is one of the early vlunerable region during AD progression. Therefore finding the correlation coefficient between early phenomen of APP processing and one of ther earlier vlunerable area of nervous system might lead to valueable insights.This research has focused on APP processing in peripheral structures, the olfactory epithelium(OE), as well as CNS structures responsible for processing of incoming olfactory signals such as olfactory bulb(OB). The present get found unique APP processing in OE that has significance in providing not only possible biomarkers (including 25kDa, 55kDa and 80kDa) that can be used for screening and detection of AD before plaque formation but also for treatment purpose. Additionally, PS2 increased level was found i n OE that possibly involved in unique APP processing and might also be crucial for understanding the -secretase role and controlling AD through -secretase as a therapeutic target.Table 1. Secretases responsible for APP processing. existent AND METHODSMATERIAL AND METHODS1.1. Animal1.1 .1. Transgenic Alzheimers disease theoretical account Tg2576 miceIn this study, heterozygous Tg2576 mice were used, which express a human amyloid- precursor protein (APP) variant linked to Alzheimer disease, as actual and described previously 21.Age-matched non-transgenic littermates were served as wild-type control. All animal experiments were approved and conducted in accordance with guidelines of Ethic Committee of Seoul National University DGIST.Transgenic Alzheimers disease model Tg6799 miceAnother AD model used in this study was Tg6799 mice, which expresses human amyloid precursor protein (APP) with three familial Alzheimers disease point mutations and two human presenilin1 mutations thus als o known as 5x FAD mice. Both of these mutation types mainly contribute to increased production of A42 22. Age-matched non-transgenic littermates were served as wild-type control. All animal experiments were approved and conducted in accordance with guidelines of Ethic Committee of Seoul National University DGIST.Table2. Transgenic models used for this study.olfactory carriageal analysisFood buried, behavior test was performed to measure the mice smell ability to find a buried food pellet using olfactory cues as previously described 23 24 25 26. Olfactory test was taken blindly without revealing any genotypic information of mice before and during the experiment. Mice were deprived of food around 35 hours with free access to water. onward starting the experiment, adaptation time was provided 510 min to let them adapt in new prepared cage with new bedding material. This whole tone was important for mice to be adapted to the new environment so that they would able to focus on findin g food in a new environment. resembling cage were prepared with bedding material depth approximately 5 cm and food pellet was buried 2.5 cm below the surface. Latency or cut-off time 15 min maximum was provided to each mice to find buried food. Latency time was recorded, as time between mouse inserted into the cage and greedy the food pellet, precisely using video tracking software and system (EthoVision xt 9).