S100A7, a novel Alzheimer's disease biomarker with non-amyloidogenic alpha-secretase activity acts via selective promotion of ADAM-10.
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.
Qin
Weiping
W
Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA.
Ho
Lap
L
Wang
Jun
J
Peskind
Elaine
E
Pasinetti
Giulio Maria
GM
D051722:ADAM Proteins / Q000097:blood* / Q000378:metabolism; D000072197:ADAM10 Protein; D000544:Alzheimer Disease / Q000097:blood* / Q000378:metabolism; D000682:Amyloid / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000097:blood* / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000097:blood* / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism; D016466:CHO Cells; D002135:Calcium-Binding Proteins / Q000097:blood* / Q000378:metabolism; D016022:Case-Control Studies; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D008565:Membrane Proteins / Q000097:blood* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D000682:Amyloid; D015415:Biomarkers; D002135:Calcium-Binding Proteins; D008565:Membrane Proteins; D010455:Peptides; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins; C089242:S100A7 protein, human; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human