부산대학교 도서관

Several novel transgenic mouse models expressing different mutant APPs in combination with mutant PS1 have been developed. These models have been analyzed to investigate the formation and progressive alterations of dystrophic neurites (DNs) in relation to Aβ deposits. In the most aggressive model, Aβ deposits appear as early as 2.5 months of age. Maturation of DNs was qualitatively quite similar among models and in some respect reminiscent of human AD pathology. From the onset of deposition, most if not all Aβ deposits were decorated with a high number of APP-, ubiquitin-, and MnSOD-immunoreactive DNs. Phosphorylated Tau DNs, however, appeared at a much slower rate and were more restricted. Mitochondrial dysfunction markers were observed in DNs: the frequency and the density per deposit of DNs accumulating cytochrome c, cytochrome oxidase 1, and Bax progressively increased with age. Later, the burden of reactive DNs was reduced around large compact/mature deposits. In addition, the previously described phenomenon of early intraneuronal Aβ accumulation in our models was associated with altered expression of APP protein as well as oxidative and mitochondrial stress markers occasionally in individual neurons. The present study demonstrates that oxidative and mitochondrial stress factors are present at several phases of Aβ pathology progression, confirming the neuronal dysfunction in APP transgenic mice. [Copyright &y& Elsevier]