S100A7, a Novel Alzheimer's Disease Biomarker with Non-Amyloidogenic α-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 β-amyloid (Aβ)1–42 and Aβ1–40 peptides, coincidental with a selective promotion of “non- amyloidogenic” α-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 α-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 α-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

Alteration of Aβ metabolism-related molecules in predementia induced by AlCl3 and d-galactose

The purpose of this study was to look for alterations in β-amyloid peptide (Aβ) metabolism-related molecules in predementia, the early stage of Alzheimer’s disease (AD). AlCl3 (Al) and d-galactose (D-gal) were used to induce the mouse model for predementia and AD. Protein expression of β-amyloid (Aβ), β-secretase (BACE1), neprilysin (NEP), insulin degrading enzyme (IDE) and receptor for advanced glycation end products (RAGE) in the brain was measured. The results indicated that Al + D-gal induced an AD-like behavioral deficit at 90 days. The period from 45 to 75 days showed no significant behavioral deficit, and we tentatively define this as predementia in this model. A significant increase in BACE1 and decreasing NEP characterized days 45–90 in the cortex and hippocampus. However, high Aβ occurred at day 60. IDE increased from day 60 to day 75. There was no change in RAGE. The results suggest that the observed changes in BACE1, NEP and Aβ in predementia might relate to a different stage of the AD-like pathology, which may be developed into useful biomarkers for the diagnosis of very early AD