Journal Article

S100A7, a Novel Alzheimer's Disease Biomarker with Non-Amyloidogenic α-Secretase Activity Acts via Selective Promotion of ADAM-10

Pasinetti, Giulio Maria, Peskind, Elaine, Wang, Jun, Ho, Lap, Qin, Weiping

2009

Overview

Alzheimer's disease (AD) is the most common cause of dementia among older people. At present, there is no cure for the disease and as of now there are no early diagnostic tests for AD. There is an urgency to develop a novel promising biomarker for early diagnosis of AD. Using surface-enhanced laser desorption ionization-mass spectrometry SELDI-(MS) proteomic technology, we identified and purified a novel 11.7-kDa metal- binding protein biomarker whose content is increased in the cerebrospinal fluid (CSF) and in the brain of AD dementia subjects as a function of clinical dementia. Following purification and protein-sequence analysis, we identified and classified this biomarker as S100A7, a protein known to be involved in immune responses. Using an adenoviral-S100A7 expression system, we continued to examine the potential role of S100A7 in AD amyloid neuropathology in in vitro model of AD. We found that the expression of exogenous S100A7 in primary cortico-hippocampal neuron cultures derived from Tg2576 transgenic embryos inhibits the generation of beta-amyloid (Abeta)(1-42) and Abeta(1-40) peptides, coincidental with a selective promotion of \"non- amyloidogenic\" alpha-secretase activity via promotion of ADAM (a disintegrin and metalloproteinase)-10. Finally, a selective expression of human S100A7 in the brain of transgenic mice results in significant promotion of alpha-secretase activity. Our study for the first time suggests that S100A7 may be a novel biomarker of AD dementia and supports the hypothesis that promotion of S100A7 expression in the brain may selectively promote alpha-secretase activity in the brain of AD precluding the generation of amyloidogenic peptides. If in the future we find that S1000A7 protein content in CSF is sensitive to drug intervention experimentally and eventually in the clinical setting, S100A7 might be developed as novel surrogate index (biomarker) of therapeutic efficacy in the characterization of novel drug agents for the treatment of AD.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: ADAM protein / ADAM Proteins - blood / ADAM Proteins - metabolism / ADAM10 Protein / Alzheimer Disease - blood / Alzheimer Disease - metabolism / Alzheimer's disease / Alzheimers disease / Amino acid sequence / Amyloid - metabolism / Amyloid Precursor Protein Secretases - blood / Amyloid Precursor Protein Secretases - metabolism / Amyloidogenesis / Animals / Biomarkers / Biomarkers - blood / Biomarkers - metabolism / Blood Platelets - metabolism / Brain / Brain research / Calcium-Binding Proteins - blood / Calcium-Binding Proteins - metabolism / Case-Control Studies / Cell Biology/Developmental Molecular Mechanisms / Cerebrospinal fluid / CHO Cells / Clinical trials / Cognitive ability / Cognitive impairment / Cricetinae / Cricetulus / Dementia / Dementia disorders / Diagnostic systems / Embryos / Enzymes / Family medical history / Geriatrics / Hippocampus / Humans / Hypotheses / Immune response / Intervention / Ionization / Kinases / Laboratories / Mass spectrometry / Mass spectroscopy / Medicine / Membrane Proteins - blood / Membrane Proteins - metabolism / Neurodegenerative diseases / Neurological Disorders/Alzheimer Disease / Neuropathology / Neuroscience / Neurosciences / Older people / Peptides / Peptides - chemistry / Promotion / Protein purification / Proteins / Psychiatry / S100 Calcium Binding Protein A7 / S100 Proteins / Secretase / Signal transduction / Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Transgenic mice / β-Amyloid