Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor prote

Abstract

Genetic causes of Alzheimer's disease (AD) include mutations in the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (P52) genes1. The mutant APPK670N,M67M transgenic line, Tg2576, shows markedly elevated amyloid β-protein (AP) levels at an early age and, by 9–12 months, develops extracellular AD-type Ap deposits in the cortex and hippocampus2. 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 Aβ342(43) (ref. 3). Here we demonstrate that the doubly transgenic progeny from a cross between line Tg2576 and a mutant PS1M46L transgenic line develop large numbers of fibrillar Aβ deposits in cerebral cortex and hippocampus far earlier than their singly transgenic Tg2576 litter-mates. In the period preceding overt Aβ deposition, the doubly transgenic mice show a selective 41% increase in Aβ42(43) in their brains. Thus, the development of AD-like pathology is substantially enhanced when a P51 mutation, which causes a modest increase in Aβ42(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 Aβ 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.

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Holcomb, L., Gordon, M., McGowan, E. et al. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 4, 97–100 (1998). https://doi.org/10.1038/nm0198-097

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