Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Holcomb, L. et al.

Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes.

Genetic causes of Alzheimer's disease (AD) include mutations in the amyloid precursor protein ( APP), presenilin 1 ( PS1), and presenilin 2 ( PS2) genes. The mutant APP(K670N,M671L) transgenic line, Tg2576, shows markedly elevated amyloid beta-protein (A beta) levels at an early age and, by 9-12 months, develops extracellular AD-type A beta deposits in the cortex and hippocampus. Mutant PS1 transgenic mice do not show abnormal pathology, but do display subtly elevated levels of the highly amyloidogenic 42- or 43-amino acid peptide A beta42(43). Here we demonstrate that the doubly transgenic progeny from a cross between line Tg2576 and a mutant PS1M146L transgenic line develop large numbers of fibrillar A beta deposits in cerebral cortex and hippocampus far earlier than their singly transgenic Tg2576 littermates. In the period preceding overt A beta deposition, the doubly transgenic mice show a selective 41% increase in A beta42(43) in their brains. Thus, the development of AD-like pathology is substantially enhanced when a PS1 mutation, which causes a modest increase in A beta42(43), is introduced into Tg2576-derived mice. Remarkably, both doubly and singly transgenic mice showed reduced spontaneous alternation performance in a "Y" maze before substantial A beta deposition was apparent. This suggests that some aspects of the behavioral phenotype in these mice may be related to an event that precedes plaque formation.[1]

References

Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Holcomb, L., Gordon, M.N., McGowan, E., Yu, X., Benkovic, S., Jantzen, P., Wright, K., Saad, I., Mueller, R., Morgan, D., Sanders, S., Zehr, C., O'Campo, K., Hardy, J., Prada, C.M., Eckman, C., Younkin, S., Hsiao, K., Duff, K. Nat. Med. (1998) [Pubmed]

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