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Abstract: Accumulation of aggregated amyloid β-protein (Aβ) in the brain is thought to be the initiating event leading to neurodegenetation and dementia in Alzheimer''s disease (AD). Therefore, therapeutic strategies that clear accumulated Aβ and/or prevent Aβ production and its aggregation are predicted to be effective against AD. Immunization of AD mouse models with synthetic Aβ prevented or reduced Aβ load in the brain and ameliorated their memory and learning deficits. The clinical trials of Aβ immunization elicited immune responses in only 20% of AD patients and caused T-lymphocyte meningoencephalitis in 6% of AD patients. In attempting to develop safer vaccines, we previously demonstrated that an adenovirus vector, AdPEDI-(Aβ1–6)11, which encodes 11 tandem repeats of Aβ1-6 can induce anti-inflammatory Th2 immune responses in mice. Here, we investigated whether a DNA prime-adenovirus boost regimen could elicit a more robust Th2 response using AdPEDI-(Aβ1–6)11 and a DNA plasmid encoding the same antigen. All mice (n =7) subjected to the DNA prime-adenovirus boost regimen were positive for anti-Aβ antibody, while, out of 7 mice immunized with only AdPEDI-(Aβ1–6)11, four mice developed anti-Aβ antibody. Anti-Aβ titers were indiscernible in mice (n =7) vaccinated with only DNA plasmid. The mean anti-Aβ titer induced by the DNA prime-adenovirus boost regimen was approximately 7-fold greater than that by AdPEDI-(Aβ1–6)11 alone. Furthermore, anti-Aβ antibodies induced by the DNA prime-adenovirus boost regimen were predominantly of the IgG1 isotype. These results indicate that the DNA prime-adenovirus boost regimen can enhance Th2-biased responses with AdPEDI-(Aβ1–6)11 in mice and suggest that heterologous prime-boost strategies may make AD immunotherapy more effective in reducing accumulated Aβ. [Copyright &y& Elsevier]

Abstract: A total of 45 different mutations of methyl-CpG-binding protein 2 gene (MECP2) were identified in 145 of 219 Japanese patients with typical or atypical Rett syndrome (RTT) (66.2%). A missense mutation, T158M was the most common mutation of MECP2, identified in 22 (19.1%) patients, followed by four nonsense mutations, R168X (14.8%), R270X (13.0%), R255X (9.6%), and R294X (6.1%) in 115 patients with classical RTT. Two missense mutations, R133C (33.3%) and R306C (23.3%), and a nonsense mutation, R294X (13.3%), were common in 30 patients with atypical RTT, including the preserved speech variant (PSV). Frameshift mutations due to nucleotide deletion or insertion were identified in 22 patients with MECP2 mutations, and one of them had a 3.6kb deletion encompassing exons 3 and 4. Three patients with classical RTT had a splicing anomaly. The wide spectrum of phenotypic variability in patients with RTT has been considered to be correlated with the mutation type and location in MECP2, and X-inactivation. However, most patients showed a random X-inactivation pattern evaluated by an androgen receptor gene polymorphism in this study, suggesting that a skewed X-inactivation might not be a main modification factor on clinical phenotypes of RTT. In addition, three new missense mutations, P176R, A378V and T479M, were identified in patients with RTT, but also in healthy Japanese, indicating that these mutations are non-pathogenic in Japanese. Information about rare polymorphic variations is very important for the molecular diagnosis of RTT, although rare polymorphic variants might differ among ethnic groups. [Copyright &y& Elsevier]