used macrophage specific expression of a dominant negative form of TGF B in APP AD mice, expression in microglia was absent. Ablation of macrophage TGF B signaling mark edly inhibited disease development, confirming that macrophages alone can play a determinant selleck chem inhibitor role in AD disease development. For recent reviews on macro phage recruitment into AD brain see. The central involvement of the immune system unavoidably prompts the question of whether some infectious component might contribute to disease development in ATH and or AD. The idea Inhibitors,Modulators,Libraries that a common disease condition might have an infectious component is not new. Although initially challenged, Warren and Marshall in 1984 observed that biopsy specimens of patients with gastric ulcers contained spiral or curved bacteria, Inhibitors,Modulators,Libraries and received the Nobel prize for their discovery that Helicobacter pylori is a cause of gastric ulcers.
Transmissibility of AD AD has features of transmissibility. There is intriguing evidence that pathology spreads progressively through the brain from initial foci. Inhibitors,Modulators,Libraries Duff and colleagues re port that Tau pathology in human AD brain commences in the entorhinal cortex and spreads trans synaptically from cell to cell. Similar findings were reported in mice by de Calignon et al. who expressed a mutant form of human Tau that predisposes to AD like pathology in the entorhinal cortex. Pathology propagated from transgene expressing neurons to adjacent brain regions lacking any detectable transgene expression. There is direct evidence of transmissibility.
Marmosets Inhibitors,Modulators,Libraries do not normally develop AD pathology but, when injected intracerebrally with brain tissue from a patient with early onset AD, animals developed AD like amyloid plaques 6 7 years after inoculation. Non AD brain tissue failed to transmit disease and the induced degeneration was transmissible to further animals. Further evidence for transmissibility emerges from APP transgenic models in which mice develop AD like path ology only late in life. Disease onset was remarkably accelerated by inoculation of extracts of human AD brain into young APP AD transgenic mice. Using 10% w v brain homogenates from postmortem AD patients, Meyer Luehmann et al. demonstrated that inoculation into young transgenic mice induced robust deposition of AB, whereas non AD brain failed to do so.
Similar seeding has been reported when brain extracts from older APP trans genic mice are injected into young transgenic animals. Inhibitors,Modulators,Libraries Parallel observations have been reported in transgenic mice and rats that do not alone develop dis ease. Although classic AD like Tau pathology is generally absent, marking differences between human and murine Tau, NFT were induced when extracts of transgenic mouse Rapamycin order AD brain were inoculated into trans genic APP AD mice expressing mutant Tau.