Pretreatment of animals with 3,6 especially dithiothalidomide markedly inhibited each of these aspects and, together with our prior studies, suggested that Inhibitors,Modulators,Libraries the agent Inhibitors,Modulators,Libraries could prove of value in Tg models of AD that, like the human condition, increasingly develop neu roinflammation during disease progression. This hypothesis was tested in two cohorts of 3xTg AD mice of 10 and 17 months age, chosen to represent times that in our specific line coincided with the pre and post development of amyloid plaques and neurofibrillary tan gles, as the presence of activated microglia in close prox imity to amyloid plaques is a cardinal feature of AD afflicted brain. The pre pathological upregulation of TNF and asso ciated enhancement of activated microglia have been reported in the 3xTg AD mouse model, and it has been postulated that these activated immune cells are key in the process of clearing extracellular AB.

A potential consequence of heightened AB exposure, however, is microglia TLR4 stimulation and a resultant upregulation of cytokine production and release. TNF as well as IL 1B can correspondingly elevate AB generation by stimulating secretase activity, po tentially spawning a self propagating positive feedback loop of AB induction of inflammation Inhibitors,Modulators,Libraries and TNF signal ing that, in turn, may provoke further AB generation. In our study, in accord with the literature, activated microglia were markedly elevated in Inhibitors,Modulators,Libraries old versus adult vehicle treated 3xTg AD mice, which additionally presented with a significant elevation in brain AB142 and phosphorylated tau levels, a decline in total tau and a trend towards elevation of APP levels.

A substantial accumulation of extracellular amyloid plaques was clearly evident within the cerebral cortex and hippocampus of old versus adult 3xTg Inhibitors,Modulators,Libraries AD mice, which was accompanied by deficits in learning and memory, as assessed within the Morris Water Maze paradigm. The administration of 3,6 dithiothalidomide to old 3xTg AD mice reversed each of these parameters, significantly reducing AB142, phos phorylated tau and APP levels, lowering levels of acti vated microglia and fully ameliorating memory deficits, which were accompanied by an eleva tion in synaptic protein markers. These drug induced changes are in line with studies by McAlpine and colleagues, demonstrating that block ade of TNF signaling significantly sup pressed AD pathology. Importantly, our studies add itionally demonstrate that cognitive deficits that accompany the classical pathology selleck catalog of AD appear to be reversible, at least in the 3xTg AD mouse model. A caveat with this 3xTg AD mouse model, like all such models, is that it provides a partial model of the human dis ease.