This assemblage is regulated by signals from the the scavenger receptor CD36 [34]. These data show that CD36-TLR4-TLR6 activation is a common molecular mechanism by which atherogenic lipids and A?? stimulate an inflammatory response in arteriosclerosis and AD, respectively. Arteriosclerosis is a major risk factor for late-onset AD and the discussed findings suggest that both disorders share a common pathogenic mechanism rooted in the innate immune system. Introducing a functionally destructive mutant of TLR4 into a transgenic mouse model (APPswe/PS1) results in increased levels of A?? deposits, as well as reduced microglia activity [35]. Microglia from CD14 null mice failed to affect A??l-42 damaged neurons and neuronal survival was accompanied by a significant reduction in the production of IL-6, indicative of reduced microglial activation [36].

All these data suggest that activation of TLR4 and CD14 signaling is involved in both the detrimental production of pro-inflammatory cytokines as well as the beneficial removal of A?? in AD, illustrating the two-edged sword aspect of the neuroinflammatory response in AD brains [37]. Experimental animal studies indicate that microglia ‘acivation’ is not simply one phenotypic manifestation but includes heterogeneous, functional phenotypes that range from a pro-inflammatory, classic activation state to an alternative activation state involved in repair and extracellular matrix remodeling [38,39]. Lipopolysaccharide (LPS), a bacterial coat component, is widely used as a potent stimulator of the innate immune system and it is recognized by a receptor complex containing fully functional TLR4 and CD14.

Chronic neuroinflammation induced by LPS in rats reproduced components of the neurobiology of AD, such as increased activation of microglia and astrogliosis, increased tissue levels of IL-1 and TNF-??, elevated expression of the amyloid precursor protein, and a working memory deficit [40]. Innate immunity responsiveness can be investigated by the incubation of whole blood samples with LPS, followed by the determination of levels of various inflammatory cytokines. Twin studies demonstrate that heritability for serum levels of circulating inflammatory mediators is modest (about 20%). In contrast to circulating inflammatory mediators, however, cytokine production capacity is under strong genetic control. In the non-diseased population, estimates for the heritability of the production of the various cytokines ranges from 53 to 86% [41]. We have studied Carfilzomib Palbociclib Phase 3 cytokine production capacity in ex vivo stimulated full blood samples from middle aged off spring with and without a parental history of late-onset AD [42].