Microglial activation is a key feature in Alzheimer’s disease and is considered to contribute to progressive neuronal injury by release of neurotoxic products. The innate immune receptor Toll-like-receptor 4 (TLR4), localized on the surface of microglia, is a first-line host defense receptor against invading microorganisms. Here, we show that a spontaneous loss-of-function mutation in the Tlr4 gene strongly inhibits microglial and monocytic activation by aggregated Alzheimer amyloid peptide resulting in a significantly lower release of the inflammatory products IL-6, TNFα and nitric oxide. Treatment of primary murine neuronal cells with supernatant of amyloid peptide-stimulated microglia demonstrates that Tlr4 contributes to amyloid peptide-induced microglial neurotoxicity. In addition, stimulation experiments in transfected HEK293 cells allowed to define a tri-molecular receptor complex consisting of TLR4, MD-2 and CD14 necessary for full cellular activation by aggregated amyloid peptide. A clinical relevance of these findings is supported by a marked upregulation of Tlr4 mRNA in APP transgenic mice and by an increased expression of TLR4 in Alzheimer’s disease brain tissue associated with amyloid plaque deposition. Together, these observations provide the first evidence for a role of the key innate immune receptor, TLR4, in neuroinflammation in Alzheimer’s disease.

To rapidly respond to invading microorganisms, humans call on their innate immune system. This occurs by microbe-detecting receptors, such as CD14, that activate immune cells to eliminate the pathogens. Here, we link the lipopolysaccharide receptor CD14 with Alzheimer`s disease, a severe neurodegenerative disease resulting in dementia. We demonstrate that this key innate immunity receptor interacts with fibrils of Alzheimer amyloid peptide. Neutralization with antibodies against CD14 and genetic deficiency for this receptor significantly reduced amyloid peptide induced microglial activation and microglial toxicity. The observation of strongly enhanced microglial expression of the LPS receptor in brains of animal models of Alzheimer's disease indicates a clinical relevance of these findings. These data suggest that CD14 may significantly contribute to the overall neuroinflammatory response to amyloid peptide, highlighting the possibility that the enormous progress currently being made in the field of innate immunity could be extended to research on Alzheimer's disease.

Cerebral cholesterol metabolism has been linked with production of amyloid peptide (Abeta) crucial in AD. The association between use of cholesterol-lowering drugs (statins) and AD disease is currently being intensely discussed. In this case-control study on elderly nondemented subjects, the authors provide the first evidence that statins in clinically relevant dosages indeed affect cerebral cholesterol metabolism. However, these changes were not associated with altered intrathecal secretion of Alzheimer Abeta.

The boundary zone between two Penninic nappes, the eclogite-facies to ultrahigh-pressure Zermatt-Saas zone in the footwall and the blueschistfacies Combin zone in the hanging wall, has been interpreted previously as a major normal fault reflecting synorogenic crustal extension. Quartz textures of mylonites from this fault were measured using neutron diffraction. Together with structural field observations, the data allow a refined reconstruction of the kinematic evolution of the Pennine nappes. The main results are:(1) the contact is not a normal fault but a major thrust towards northwest which was only later overprinted by southeast-directed normal faulting; (2) exhumation of the footwall rocks did not occur during crustal extension but during crustal shortening; (3) the Sesia-Dent Blanche nappe system originated from a continental fragment (Cervinia) in the Alpine Tethys ocean, and the Combin zone ophiolites from the ocean basin southeast of Cervinia; (4) out-of-sequence thrusting played a major role in the tectonic evolution of the Penninic nappes.

10 090 dissections of dogs exhibited 2631 neoplastic processes of which 309 involved the heart in the form of eu-and heteropic tumours. The most common primary and/or secondary heart tumour type was hemangiosarcoma (n = 187), followed by paraganglioma (n = 46), carcinoma (n = 33), malignant lymphoma (n = 12), thyroid heart base tumour (n = 9), melanoma (n = 7), mast cell tumour (n = 3) and blastoma (n = 2). The tumour diagnoses were immunohistochemically proved by various antibodies to cytokeratins, vimentin, GFAP, NSE, von Willebrand factor, CD3, CD45RA, S100, thyroglobulin as well as histochemically with argyrophilic, Fontana-Masson and heterochromatic reactions. The odds ratio (OR) for breed and tumour prevalences were determined: German shepherds showed the highest OR for hemangiosarcomas and boxers for paragangliomas.