Cycle 1 project 1

Transmembrane protein x in relation to early stages of Alzheimer’s disease


PhD student: Marta Del Campo Milan, Spain
Home Institute:Amsterdam Neuroscience; Principle Investigator; Charlotte Teunissen
Host Institute: Center for Neuroscience and Cell Biology (University of Coimbra); Principle Investigator: Oliveira, Catarina

Executive Summary
A biomarker is a characteristic that is objectively measured as an indicator of normal and pathogenic processes, or responses to a therapeutic intervention. For brain diseases, cerebrospinal fluid (CSF) is the body fluid of choice for biomarker analysis since it is in direct contact with the brain tissue, and therefore provides a unique window into ongoing local pathology. The measurement of amyloid beta(Abeta)1-42 protein, combined with tau and phosphorylated tau proteins in CSF has proven to be very valuable for diagnosis of Alzheimer’s disease (AD). However, these markers can identify AD in patients with mild cognitive impairment (MCI) only with reasonable accuracy (Mattson 2009) and have limited value for prognosis. Therefore, novel biomarkers are needed for early diagnosis of AD and prognosis.

Novel discovery-based technologies, such as proteomics, can identify and quantify large numbers of peptides and proteins simultaneously. We have recently developed and validated a promising method for in-depth analysis of the CSF proteome by a combination of abundant protein depletion, one-dimensional gel electrophoresis and nano-liquid chromatography-mass spectrometry. In a study comparing CSF of 5 controls, 5 MCI patients converting to AD, 5 MCI patients not converting to AD, and 5 AD patients we successfully identified several discriminatory biomarkers.

One of the proteins, is a transmembrane protein, (named x as we currently apply for patents). The gene coding for this protein is a familial dementia gene. Levels were increased 4-fold in AD patients. The levels of this protein in MCI patients converting to AD were similar to the levels of AD patients, while levels in MCI non-converters were alike the control levels. These data indicate that this protein x is a promising candidate biomarker for early diagnosis of AD. Very little information is available about this protein. Members of the family this protein belongs to have been shown to interact with APP and to serve as an endogenous negative regulator of Abeta production. The aim of this project is further elaborate the use of this transmembrane protein x for early diagnosis of AD. Furthermore, as diagnostic/state markers are required to have a relation with the pathology (Working group Neurobiology of Disease 1998) and no such information is available for this protein x, we wish to gain knowledge of the relation of this protein with the disease pathology in AD, specifically in relation to oxidative stress.

We will take advantage of available resources at the Alzheimer Center VUmc, such as welldefined cohorts of CSF samples of AD patients and controls, extensive expertise in assay development, well-characterized post-mortem sections of AD patients, and experimental systems using in vitro cultured human microglia and neurons. Collaboration with Prof Oliveira offers the opportunity to perform a cross-validation of the diagnostic test in a well defined cohort collected at Coimbra. Furthermore, as Prof Oliveira is an expert on oxidative stress biomarkers, this collaboration offers an unique opportunity to study the relation of this protein x with various oxidative stress markers directly in human plasma and CSF.

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