ACCELERATED ALZHEIMER-TYPE PHENOTYPE IN TRANSGENIC MICE CARRYING BOTHMUTANT AMYLOID PRECURSOR PROTEIN AND PRESENILIN-1 TRANSGENES

Genetic causes of Alzheimer's disease (AD) include mutations in the am yloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (P S2) genes(1). The mutant APP(K670N,M671L) transgenic line, Tg2576, sho ws markedly elevated amyloid beta-protein (A beta) levels at an early age and, by 9-12 months, develops extracellular AD-type A beta deposit s in the cortex and hippocampus(2). 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 beta 42(43) (ref. 3). Here we demonstrate that the doubly transgenic progeny from a cros s between line Tg2576 and a mutant PS1(M146L) transgenic line develop large numbers of fibrillar A beta deposits in cerebral cortex and hipp ocampus far earlier than their singly transgenic Tg2576 littermates. I n the period preceding overt A beta deposition, the doubly transgenic mice show a selective 41% increase in A beta 42(43) in their brains. T hus, the development of AD-like pathology is substantially enhanced wh en a PS1 mutation, which causes a modest increase in A beta 42(43), is introduced into Tg2576-derived mice. Remarkably, both doubly and sing ly transgenic mice showed reduced spontaneous alternation performance in a ''Y'' maze before substantial A beta deposition was apparent. Thi s suggests that some aspects of the behavioral phenotype in these mice may be related to an event that precedes plaque formation.