Overexpression of human S100B exacerbates cerebral amyloidosis and gliosis in the Tg2576 mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is the most common progressive dementia and is pathologically characterized by brain deposition of amyloid-beta (Abeta) peptide as senile plaques. Inflammatory and immune response pathways are chronically activated in AD patient brains at low levels, and likely play a role in disease progression. Like microglia, activated astrocytes produce numerous acute-phase reactants and proinflammatory molecules in the AD brain. One such molecule, S100B, is highly expressed by reactive astrocytes in close vicinity of beta-amyloid deposits. We have previously shown that augmented and prolonged activation of astrocytes has a detrimental impact on neuronal survival. Furthermore, we have implicated astrocyte-derived S100B as a candidate molecule responsible for this deleterious effect. To evaluate a putative relationship between S100B and AD pathogenesis, we crossed transgenic mice overexpressing human S100B (TghuS100B mice) with the Tg2576 mouse model of AD, and examined AD-like pathology. Brain parenchymal and cerebral vascular beta-amyloid deposits and Abeta levels were increased in bigenic Tg2576-huS100B mice. These effects were associated with increased cleavage of the beta-C-terminal fragment of amyloid precursor protein (APP), elevation of the N-terminal APP cleavage product (soluble APPbeta), and activation of beta-site APP cleaving enzyme 1. In addition, double transgenic mice showed augmented reactive astrocytosis and microgliosis, high levels of S100 expression, and increased levels of proinflammatory cytokines as early as 7-9 months of age. These results provide evidence that (over)-expression of S100B acts to accelerate AD-like pathology, and suggest that inhibiting astrocytic activation by blocking S100B biosynthesis may be a promising therapeutic strategy to delay AD progression.. (c) 2009 Wiley-Liss, Inc.