Overexpression of the neuritotrophic cytokine S100β precedes the appearance of neuritic β-amyloid plaques in APPV717F mice

Homozygous APPV717F transgenic mice overexpress a human beta-amyloid precursor protein (beta APP) minigene encoding a familial Alzheimer's disease mutation. These mice develop Alzheimer-type neuritic beta-amyloid plaques surrounded by astrocytes, S100 beta is an astrocyte-derived cytokine that promotes 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-related increases in tissue levels of both beta APP and S100 beta mRNA in transgenic mice. Neuronal beta APP overexpression was found in cell somas in young mice, whereas older mice showed beta APP overexpression in dystrophic neurites in plaques. These age-related changes were accompanied by progressive increases in S100 beta expression, as determined by S100 beta load (percent immunoreactive area). These increases were evident as early as 1 and 2 months of age, months before the appearance of beta-amyloid deposits in these mice. Such precocious astrocyte activation and S100 beta overexpression are similar to our earlier findings in Down's syndrome. Accelerated age-related overexpression of S100 beta may interact with age-associated overexpression of mutant beta APP in transgenic mice to promote development of Alzheimer-like neuropathological changes.