Biomarkers for Alzheimer’s Disease Progression

Biomarkers for Alzheimers Disease ProgressionAlzheimers disorder is slow progressive and irreversible brain disease which is angiotensin-converting enzyme of the most unwashed ca white plague of dementia 1. In AD patients not only persist from cognitive notwithstanding in any case motor and sensory loss 2. Although the chemical mechanism of AD is not well understood still AD pathology is characterized by extra cellular gritty- deposits and interacellular neurfibril tangles lickation of hyperphosphorylation of tau protein. Being irreversible and neurological alter disease, its very important to detect and diagonse at earlier or at some controlable season point. Some useful AD diagonstic biomarkers are required 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 symptom and severity of disease 3. Recent research on use of specific AD biomarker for disease staging in vivo shows that A dynamically correlates with disease at different stages of disease progression4 5. But A take aim varies in patients. Which suggests, done process of A production starts earlier but A as a biomarker only is not relibale, therefore utility(a) biomarker must be found on with A generation process.Figure1. Biomakers and AD early detectionSource Modified from Ingelsson, M et al 2004. 4A can be produced through proteolytic processing of APP (amyloid precursor protein), which takes rudimentary position in AD pathogenesis. APP is single-pass transmembrane protein with larger ectodomain. Although the physiological 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 secreta ses -secretase and -secretase dapple in amyloidogenic processing -secretase (identified as transmembrane aspartase protease BACE1) and -secretase are mixed. Product generated during both processings have soluble ectodomain (sAPP and sAPP ) respectively along with identical product called AICD (intracellular C-terminal fregmenets)9. much 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 ( enter 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 deadly 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 nerv ous body. More vlunerable areas are gauge to be effected earlier to others, the reason AD smptoms appear in different regions in a sequential order and consistency, although meachnism is poorly understood. bug 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 induceing the correlation mingled with 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 trusty for processing of incoming olfactory signals such as olfactory bulb(OB). The prove study 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 wake and detection of AD before plaque formation but also for treatment purpo se. Additionally, PS2 increased level was found in OE that possibly involved in unique APP processing and might also be essential for understanding the -secretase role and controlling AD through -secretase as a therapeutic target.Table 1. Secretases responsible for APP processing.MATERIAL AND METHODSMATERIAL AND METHODS1.1. Animal1.1 .1. Transgenic Alzheimers disease model Tg2576 miceIn this study, heterozygous Tg2576 mice were used, which express a gay amyloid- precursor protein (APP) variant linked to Alzheimer disease, as developed 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 value-system Committee of Seoul National University DGIST.Transgenic Alzheimers disease model Tg6799 miceanother(prenominal) AD model used in this study was Tg6799 mice, which expresses human amyloid precursor protein (APP) with three familial Alzheimers disease poi nt mutations and two human presenilin1 mutations thus also known as 5x FAD mice. both(prenominal) 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 value-system Committee of Seoul National University DGIST.Table2. Transgenic models used for this study.Olfactory behavioral synopsisFood bury, 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 revelation any genotypic information of mice before and during the experiment. Mice were deprived of food round 35 hours with free access to water. Before starting the experiment, adaptation time was provided 510 min to let them adapt in unused prepared chicken coop with new bedding material. This step was important for mice to be adapted to the new environment so that they would able to focus on finding food in a new environment. Similar batting 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 grasping the food pellet, precisely using video tracking software system and system (EthoVision xt 9).