Molecular Probes Based On Peptide For Early Diagnosis Of Alzheimer's Disease And Related Imaging Techniques

Alzheimer's disease(AD)is a neurodegenerative disease which has a hidden onset and deteriorates progressively.In clinical,AD is mainly characterized by cognitive decline,irreversible memory impairment,orientating ability disorder,language dysfunction,and the like.Brain tissue autopsy showed a large amount of senile plaques formed by the aggregation of amyloid-?(A?)peptides and many neurofibrillary tangles formed by the filaments of highly phosphorylated tau proteins.It is necessary to develop sensitive and specific targeting molecular probes for the early diagnosis and monitoring of Alzheimer's disease.Most of the previous studies were based on radiolabeled chemical molecules and corresponding positron emission tomography technique.A peptide called Angiopep,not only exhibite high transcytosis capacity mediated by LRP1 to transport across the blood brain barrier,but also bind to senile plaques in our previous research.In the present study,we synthesized and evaluated a series probes based on angiopepe.The angiopep was modified with Gd contrast agent via a chemical linker called DOTA for magnetic resonance imaging.We investigated the magnetic signal intensity and relaxivity value of the probes in vitro.In vivo imaging data of APP/PS1 mice showed that the probes exhibited good affinity and contrast enhancement to?-amyloid protein deposits in APP/PS1 transgenic mice.Some previous studies reported that a few ?-amyloid targeting probes can also combine to tangles.Furthermore,the result of fluorescence staining of AD human brain with fluorophores conjugated Angiopep exhibited the tangles binding capacity.In that case,we measured the binding capacity between the probes and neurofibrillary tangles using MAPT transgenic mice.The near-infrared fluorescence intensity in the brain of 9 months MAPT mice is significantly higher than that in 3 months and negative control mice.This result was confirmed by the ex vivo microscope imaging of mice brain.X-ray computed tomography,is one of the most widely used noninvasive clinical imaging technique because of its low cost,high efficiency and high spatial resolution.Gold nanoparticles have unique physical,chemical and biological properties,which making them to be an attractive candidate for CT imaging.In the fourth charpter,we synthesised some gold nanoparticles with different sizes,and evaluate the biodistribution and metabolism of gold nanoparticles in ICR and tumor-bearing mice in vivo.We found that the concentration of gold nanoparticles in liver were much higher than in other organs,and mainly accumulated in mitochondria of liver cell in TEM analysis.It suggested that liver might play an important role in the metabolism process of gold nanoparticles.Then we modified them with some multifunctional groups for brain or tumor targeting.These works will be a foundation of CT imaging for the brain lesion in the future.In summary,we synthesized and evaluated some targeted contrast agent for magnetic resonance imaging,near-infrared fluorescent imaging and CT imaging,especially explored their capacity of targeting the lesions in brain.We found that the magnetic resonance probes and near infrared fluorescence probes based on angiopep exhibited excellent targeting and detecting abilities in vivo for APP/PS1 or MAPT transgenic mice.