Overexpression of the neuritotrophic cytokine S100 beta precedes the appearance of neuritic beta-amyloid plaques in APPV717F mice

Homozygous APPV717F transgenic mice overexpress a human beta-amyloid precur sor protein (beta APP) minigene encoding a familial Alzheimer's disease mut ation. These mice develop Alzheimer-type neuritic beta-amyloid plaques surr ounded by astrocytes, S100 beta is an astrocyte-derived cytokine that promo tes neurite growth and promotes excessive expression of beta APP. S100 beta overexpression in Alzheimer's disease correlates with the proliferation of beta APP-immunoreactive neurites in beta-amyloid plaques. We found age-rel ated increases in tissue levels of both beta APP and S100 beta mRNA in tran sgenic mice. Neuronal beta APP overexpression was found in cell somas in yo ung mice, whereas older mice showed beta APP overexpression in dystrophic n eurites in plaques. These age-related changes were accompanied by progressi ve increases in S100 beta expression, as determined by S100 beta load (perc ent immunoreactive area). These increases were evident as early as 1 and 2 months of age, months before the appearance of beta-amyloid deposits in the se mice. Such precocious astrocyte activation and S100 beta overexpression are similar to our earlier findings in Down's syndrome. Accelerated age-rel ated overexpression of S100 beta may interact with age-associated overexpre ssion of mutant beta APP in transgenic mice to promote development of Alzhe imer-like neuropathological changes.