Cerebral vascular amyloid beta-protein (Abeta) deposition, also known as cerebral amyloid angiopathy, is a common pathological feature of Alzheimer's disease. Additionally, several familial forms of cerebral amyloid angiopathy exist including the Dutch (E22Q) and Iowa (D23N) mutations of Abeta. Increasing evidence has associated cerebral microvascular amyloid deposition with neuroinflammation and dementia in these disorders. We recently established a transgenic mouse model (Tg-SwDI) that expresses human vasculotropic Dutch/Iowa mutant amyloid beta-protein precursor in brain. Tg-SwDI mice were shown to develop early-onset deposition of Abeta exhibiting high association with cerebral microvessels. Here we present quantitative temporal analysis showing robust and progressive accumulation of cerebral microvascular fibrillar Abeta accompanied by decreased cerebral vascular densities, the presence of apoptotic cerebral vascular cells, and cerebral vascular cell loss in Tg-SwDI mice. Abundant neuroinflammatory reactive astrocytes and activated microglia strongly associated with the cerebral microvascular fibrillar Abeta deposits. In addition, Tg-SwDI mouse brain exhibited elevated levels of the inflammatory cytokines interleukin-1beta and -6. Together, these studies identify the Tg-SwDI mouse as a unique model to investigate selective accumulation of cerebral microvascular amyloid and the associated neuroinflammation.

Our findings demonstrate that chronic SP600125 treatment is powerfully effective in slowing down disease progression by markedly reducing multiple pathological features and ameliorating cognitive deficits associated with AD. This study highlights the concept that active JNK actually contributes to the development of the disease, and provides critical preclinical evidence that specific inhibition of JNK activation by SP600125 treatment may be a novel promising disease-modifying therapeutic strategy for the treatment of AD.

The amyloid ␤-protein precursor (A␤PP) is best known as the parent molecule to the amyloid ␤-peptide that accumulates in the brains of patients with Alzheimer's disease. Secreted isoforms of A␤PP that contain the Kunitz proteinase inhibitor domain are analogous to the previously identified cell-secreted proteinase inhibitor known as protease nexin-2 (PN2). Although PN2͞A␤PP is enriched in brain and in circulating blood platelets, little is understood of its physiological function and potential role in disease processes outside of amyloid ␤-peptide generation. We hypothesized that the potent inhibition of certain procoagulant proteinases by PN2͞A␤PP, coupled with its abundance in platelets and brain, indicate that it may function to regulate cerebral thrombosis. Here we show that specific and modest 2-fold overexpression of PN2͞A␤PP in circulating platelets of transgenic mice caused a marked inhibition of thrombosis in vivo. In contrast, deletion of PN2͞A␤PP in A␤PP gene knockout mice resulted in a significant increase in thrombosis. Similarly, platelet PN2͞A␤PP transgenic mice developed larger hematomas in experimental intracerebral hemorrhage, whereas A␤PP gene knockout mice exhibited reduced hemorrhage size. These findings indicate that PN2͞A␤PP plays a significant role in regulating cerebral thrombosis and that modest increases in this protein can profoundly enhance cerebral hemorrhage.Alzheimer's disease ͉ hemorrhage ͉ proteinase inhibitor

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Cerebral microvascular amyloid-␤ (A␤) protein deposition is emerging as an important contributory factor to neuroinflammation and dementia in Alzheimer's disease and related familial cerebral amyloid angiopathy disorders. In particular, cerebral microvascular amyloid deposition, but not parenchymal amyloid, is more often correlated with dementia. Recently, we generated transgenic mice (Tg-SwDI) expressing the vasculotropic Dutch (E693Q)/Iowa (D694N) mutant human A␤ precursor protein in brain that accumulate abundant cerebral microvascular fibrillar amyloid deposits. In the present study, our aim was to assess how the presence or absence of fibrillar A␤ deposition in the cerebral microvasculature affects neuroinflammation in Tg-SwDI mice. Using Tg-SwDI mice bred onto an apolipoprotein E gene knock-out background, we found a strong reduction of fibrillar cerebral microvascular A␤ deposition, which was accompanied by a sharp decrease in microvascular-associated neuroinflammatory cells and interleukin-1␤ levels. Quantitative immunochemical measurements showed that this reduction of the neuroinflammation occurred in the absence of lowering the levels of total A␤40/A␤42 or soluble A␤ oligomers in brain. These findings suggest that specifically reducing cerebral microvascular fibrillar A␤ deposition, in the absence of lowering either the total amount of A␤ or soluble A␤ oligomers in brain, may be sufficient to ameliorate microvascular amyloid-associated neuroinflammation.