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A new oral vaccine for Alzheimer's disease was developed using recombinant adeno-associated virus vector carrying Aβ cDNA (AAV/Aβ). Oral administration of the vaccine without adjuvant induced the expression and secretion of Aβ1-43 or Aβ1-21 in the epithelial cell layer of the intestine in amyloid precursor protein transgenic mice. Serum antibody levels were elevated for more than six months, while T cell proliferative responses to Aβ was not detected. Brain Aβ burden was significantly decreased compared to the control without inflammatory changes. This oral AAV/Aβ vaccine seems to be promising for prevention and treatment of Alzheimer's disease.

Mutations in the human NOTCH3 gene cause cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), but the pathogenic mechanisms of the disorder remain unclear. We investigated the cytotoxic properties of mutant Notch3 using stable cell lines with inducible expression of either wild-type or two mutants p.R133C and p.C185R. We found that both mutants of Notch3 were prone to aggregation and retained in the endoplasmic reticulum (ER). The turnover rates of the mutated Notch3 proteins were strikingly slow, with half-lives greater than 6 days, whereas wild-type Notch3 was rapidly degraded, with a half-life of 0.7 days. The expression of mutant Notch3 also impaired cell proliferation compared with wild-type Notch3. In addition, cell lines expressing mutant Notch3 were more sensitive to proteasome inhibition resulting in cell death. These findings suggest that prolonged retention of mutant Notch3 aggregates in the ER decreases cell growth and increases sensitivity to other stresses. It is also possible that the aggregate-prone property of mutant Notch3 contributes to a pathogenic mechanism underlying CADASIL.

Abstract:Manganese is known to induce neurological disorders similar to parkinsonisms. A dopamine deficiency has been demonstrated in Parkinson's disease and in chronic manganese poisoning, suggesting that the mechanisms underlying the neurotoxic effects of the metal ion are related to a functional abnormality of the extrapyramidal system. However, the details have yet to be elucidated. Here we report that manganese causes characteristic internucleosomal DNA fragmentation, a biochemical hallmark of apoptosis, in PC12 cells. It was transcription dependent, relatively specific for manganese, and blocked in BcI-2-overexpressed PC12 cells.The results indicate that apoptosis may play a role in the dopaminergic neurotoxicity associated with manganese, the first metal to be reported to induce this form of cell death. The early biochemical events show the impairment of energy metabolism, and the process may require new synthesis of proteins such as c-Fos and c-Jun. In addition, manganese induces phosphorylation of c-Jun at Ser 63 and Ser73 and SEK1 /MKK4 (c-Jun N-terminal kinase kinase) at Thr258 and tyrosine phosphorylation of several proteins. These results indicate that manganese activates specific signal cascades including the c-Jun Nterminal kinase pathway. Key Words: Apoptosis-Manganese-DNA fragmentation-c-Jun N-terminal kinase/ stress-activated protein kinase-Tyrosine phosphorylation-Parkinson's disease.