Examination of soluble AB142 levels indi cated a marked age effect, with old vehicle controls expressing levels 143% of adult ones. This ele vation was fully inhibited by 3,6 dithiothalidomide, whose levels were similar to adult control and drug treated mice. Total tau protein levels were reduced in old vehicle animals selleck chem inhibitor compared to adult ones, and were unaffected by drug treatment. However, levels of phosphorylated tau pro tein presented a strong age associated rise that, similarly to soluble AB142 protein, was attenuated by drug treatment in the older group. Interestingly, the levels of two synaptic mar kers, SNAP25 and synaptophysin, which showed a trend to decline in the old vehicle control group were found to be sig nificantly elevated in old drug treated mice compared to old vehicle ones.

Immunohistochemical staining of insoluble AB plaques indicated marked plaque formation only in the old 3xTg AD mice. this AB plaque staining Inhibitors,Modulators,Libraries was dramatically reduced by drug treatment. Memory func tion, assessed by the Morris Water Maze, illustrated a deficit in learning and acquisition of the location of the hidden platform in old vehicle control mice during train ing. Probe trial data obtained 4 h fol lowing their final training session indicated that these old vehicle control animals failed to remember the loca tion of the platform, as illustrated by the low time spent within the target zone as well as by the low number of platform crossings . 3,6 Dithiothalidomide abolished this age associated memory deficit, with treated mice perform ing on par with adult vehicle control and drug treated Inhibitors,Modulators,Libraries animals.

The levels of CD68 positive microglial cells within the subiculum and CA1 brain region were quantified as a marker of the inflammatory microenvironment in the hippocampus, as these regions are among those showing the highest concentration of AB Inhibitors,Modulators,Libraries plaque staining. CD68 positive microglial cells were signifi cantly elevated in number only within old vehicle control mice, and this rise was fully abolished by the drug. Inhibitors,Modulators,Libraries Hence, treatment with 3,6 dithiothalidomide induced a marked normalization of key biochemical, learning and memory features of AD in old 3xTg AD mice. Discussion Here we demonstrate that the TNF lowering agent, 3,6 dithiothalidomide, ameliorates key Inhibitors,Modulators,Libraries aspects of neu roinflammation in multiple acute and longer term CNS rodent models.

Importantly, several of these models emulate specific cardinal characteristics of AD, selleck inhibitor and high light the complex cyclic interaction among the synthesis of TNF. the development of neuroinflammation and impact on disease progression, inducing its advance ment. Our data suggest that breaking this cycle by low ering TNF generation and neuroinflammation can favorably impact AD, as assessed at both a behavioral and biochemical level, even late during the disease course.