Development of Asparaginyl Endopeptidase-Related Cerebrospinal Fluid Markers for AD
Currently it is very difficult to predict or diagnose Alzheimer's disease (AD) because there are few reliable biomarkers for this devastating disease. We found that an enzyme named asparaginyl endopeptidase (AEP) is increased in the brain of AD patients. AEP cuts at least two proteins, amyloid precursor protein (APP) and tau, generating APP and tau fragments, and that it mediates the onset and progression of AD. In the current project, we will test whether the concentration and activity of AEP, as well as the APP and tau fragments in the cerebrospinal fluid (CSF) can serve as biomarkers for the early diagnosis of Alzheimer's disease.
The goal of the project is to find new biomarkers that can detect preclinical AD. By the time a typical patient is diagnosed with AD, the disease has been progressing for many years. Our inability to detect the disease before it has progressed to where it causes memory loss and functional decline makes it difficult to develop disease-modifying therapies for this devastating disease. It is crucial to develop biomarkers that can detect preclinical AD with the required sensitivity and specificity.
In our preliminary study, we found that AEP, a pH-controlled protease, is upregulated and activated during aging and mediates the pathogenesis of AD. The protein expression and activity of AEP is elevated in AD brains compared to control brain samples. AEP cleaves two proteins, APP and tau, in the AD brain, generating several APP and tau fragments.
Our lab is investigating the hypothesis that the level of AEP and AEP-derived APP and tau fragments in CSF can serve as early biomarkers of AD. First, we are testing whether the AEP level in the CSF of AD patients is increased compared to the control CSF. We will validate the performance of the CSF AEP protein/activity and APP/tau fragments as biomarkers for the diagnosis of AD. Then we will determine the relationship between the severity of AD and the AEP-related CSF biomarkers. We will investigate the relationship between AEP-related CSF markers and the severity of cognitive impairments, hippocampal volume, amyloid beta (Aβ) plaque accumulation, and other currently used CSF diagnostic markers such as Aβ40, Aβ42, t-tau, and p-tau. Lastly, we will validate the predictive value of AEP-related CSF biomarkers. We will investigate the longitudinal change of AEP-related CSF markers in the AD patients, and whether these novel biomarkers can discriminate among the mild cognitive impairment patients who convert to AD, develop other dementias, or remain in the MCI state.
This is an innovative project based on our most recent findings that AEP cleaves both APP and tau, mediating AD pathology. Furthermore, we have developed novel antibodies that can specifically recognize AEP-derived APP and tau fragments. Using these antibodies, we will be able to identify the new APP and tau fragments in the CSF. The results of this study will help to identify novel biomarkers for AD, facilitating the early diagnosis of AD, and hopefully promote the early intervention and prevention of AD.
About the Researcher
Zhentao Zhang, MD, PhD, is a postdoctoral research scholar in the Department of Pathology and Laboratory Medicine at Emory University. He completed his doctoral studies on neuroscience and neurology in Tongji Medical College, Huazhong University of Science and Technology (China). He joined the group of Keqiang Ye, PhD, in 2012, where he focused on the proteolytic processing of APP and tau in AD. The discovery of AEP as a novel protease that mediates the truncation of both APP and tau not only makes it a promising target for the treatment of AD, but also makes it a potential biomarker for the diagnosis of AD.
"After finishing my MD and PhD degrees, I worked in the neurology department at a hospital. A lot of patients come to the hospital with the main complication of cognitive decline. Some could not remember where they lived. Some could not recognize their family members. Almost half of them were diagnosed with Alzheimer disease.
This devastating disease poses a great challenge to their families and to society. Unfortunately, there is no cure for it because the molecular mechanisms of the disease are largely unknown. I joined Dr. Keqiang Ye’s team in the Department of Pathology and Laboratory Medicine at Emory University. Under the instruction of Dr. Ye, we identified a novel protease AEP that mediates the pathogensis of AD. We immediately came to the hypothesis that this enzyme may serve as a novel biomarker for the early diagnosis of AD. The support from BrightFocus Foundation provides us the opportunity to verify this hypothesis. We hope our findings will help facilitate early diagnosis and early intervention, and ultimately improve treatment success for patients who suffer from this illness."
First published on: July 10, 2015
Last modified on: July 1, 2017