3,6′-Dithiothalidomide (42 mg/kg i.p. once daily × 6 weeks) attenuated age-associated Aβ plaque deposition, memory deficits and indices of neuroinflammation in the subiculum and CA1 region of the hippocampus in the elder of two cohorts of 3xTg-AD mice. (A) Male 3xTg-AD mice displayed an age-dependent increase in Aβ plaque deposition; drug treatment reduced the numbers of Aβ plaques in the older (old) animals. Upper panel: in younger adult (adult) animals (approximately 11.5 months of age at the time of death) few if any Aβ plaques were detectable by immunohistochemical methods. However, in old animals (approximately 18.5 months of age at the time of death) male 3xTg-AD mice presented marked deposition of Aβ plaques that were markedly reduced by drug treatment. Representative brain sections illustrating the levels of Aβ plaque formation detected in the adult and old animals and the effects of 6 weeks of 3,6′-dithiothalidomide on plaques are shown. (B) Morris Water Maze training over 6 days with four trials per day revealed a significant interaction between age and treatment (F(1,33) = 4.77; P < 0.0360). In addition a main effect of treatment was observed F(1,33) = 5.34; P < 0.0272 (n = 7–9); specific comparisons showed that drug treatment attenuated the learning deficits observed in the old group. (C and D) Probe trial performed 4 h after the last training session on day 6 showed an interaction between age and drug treatment F(1,33) = 4.60; P < 0.0393. Treatment: F(1,33) = 4.26; P < 0.0468. This indicated that drug-treated old mice were able to remember the location of the submerged platform more akin to that of the adult mice, age and treatment for time in target zone: F(1,33) = 4.60; P < 0.0393; treatment: F(1,33) = 4.26; P < 0.0468. (E) The numbers of CD68 positive microglial cells were significantly elevated in the old vehicle-treated mice compared to the drug-treated old and both sets of adult mice. Data are expressed as mean ± SEM of n observations; levels of statistical significance are indicated as follows: *P < 0.05, **P < 0.01, ***P < 0.001.