La. Holcomb et al., Behavioral changes in transgenic mice expressing both amyloid precursor protein and presenilin-1 mutations: Lack of association with amyloid deposits, BEHAV GENET, 29(3), 1999, pp. 177-185
Mutations in the amyloid precursor protein (mAPP) and in presenilin 1 (mPS1
) have both been linked to increased production of the beta-amyloid peptide
(A beta). Doubly transgenic mice produced by mating of a parental line car
rying the "Swedish" (K670N/M671L) APP mutation with a FAD4 (M146L) mutant p
resenilin 1 line developed numerous fibrillar A beta deposits by 6 months o
f age. Prior work demonstrated that mAPP and doubly transgenic (mAPP/mPS1)
mice have deficits in Y-maze alternation behavior as early as 3 months of a
ge. Increased activity was also apparent in the mAPP/mPS1 mice at this time
point. These changes in Y-maze performance persisted in mAPP/mPS1 mice at
6 and 9 months of age. The mPS1 singly transgenic mice were not impaired on
this task at any age. Six- and nine-month-old mice were also tested for sp
atial navigation behavior in the Morris water maze. In training trials, no
differences in escape latency were detected among the four genotypes. In pr
obe trials, no differences were detected in either the time spent in the tr
ained quadrant or the number of platform crossings among the four groups. H
istological staining for A beta amyloid deposits indicates that all doubly
transgenic mice have amyloid deposits by 6 months of age (roughly 25 mice e
xamined thus far), yet no 3-month-old mice have been found with deposits. A
beta immunostaining confirmed that the 9-month-old mice tested behaviorall
y also have A beta deposits. Thus, doubly transgenic mice exhibited changes
in Y-maze performance prior to the formation of amyloid deposits, which ar
e essentially unchanged as the deposits increase in number and size to 9 mo
nths of age. Yet these mice fail to reveal impairments in spatial navigatio
n at 6 or 9 months in spite of the increasing plaque burden. These data ind
icate that A beta deposits alone are not sufficient to cause robust spatial
memory impairment in mice of this mixed background lineage and age.