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Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice

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Science  04 Oct 1996:
Vol. 274, Issue 5284, pp. 99-103
DOI: 10.1126/science.274.5284.99

Figures

  • Fig. 1.

    Brain APP immunoblot of young and old Tg+ mice and nontransgenic control mice with 6E10 (24), which recognizes human but not mouse APP, and 22C11 (Boehringer Mannheim), which recognizes both human and mouse APP. Lanes 1 to 3, nontransgenic mice; lanes 4 to 6, 73-day-old mice; lanes 7 and 8, 430-day-old mice. Detailed methods for APP quantitation were described previously (14); antibody binding was revealed with 35S-labeled protein A instead of 125I-labeled protein A.

  • Fig. 2.

    Learning and memory tests of transgenic and control mice. Asterisks indicate measures in which transgenic mice differed significantly from controls (P < 0.05). (A) The latency to escape to the hidden platform in the water maze is impaired in Tg+ mice relative to age-matched nontransgenic controls (19). Although the impairment increases with age, Tg+ mice showed a consistent trend toward longer escape latencies than those of Tg controls. (B) After 24 trials (over 6 days) with the platform in its fixed location, mice were given a probe trial in which they swam for 60 s with the platform removed. Two- and 6-month-old Tg and Tg+ mice spent significantly more than 25% of their time in the target quadrant, indicating that they had learned its location. Although 9- to 10-month-old control mice still searched selectively for the platform, older transgenic mice spent no more time in the target quadrant than in the other three quadrants, suggesting that they had not learned the platform's location (20). (C) The implications of (B) are supported by the observation that on probe trials, 9- to 10-month-old Tg+ mice crossed what had been the exact location of the platform significantly less frequently than did age-matched Tg mice. (D) The bars on the left indicate that transgenic (+) mice did not differ from control (-) mice in the total number of platform locations crossed (that is, the centers of all four quadrants); the bars on the right show the significant difference between 9- to 10-month-old transgenic mice and controls on the percentage of total platform crossings that were over the target. (E) Nine- to 10-month-old Tg+ mice were also impaired in swimming to a visible platform, although escape latencies did not differ significantly on the first visible-platform training trial. (F) Aged Tg+ mice were impaired in their tendency to spontaneously alternate arm-entry in a Y-maze, another behavioral task sensitive to hippocampal damage.

  • Fig. 3.

    Extracellular amyloid deposits in transgenic mice A01493 (age, 368 days) and A01488 (354 days) overexpressing human APP695 with the K670N,M671L mutation. (A) A01493, multiple plaques in the cerebral cortex and subiculum staining with 4G8 mAb. (B) A01493, inset from (A). (C) A01488, plaque in subiculum staining with 4G8 mAb. (D) A01488, plaque in section adjacent to (C) fails to stain with 4G8 mAb preabsorbed with Aβ(14–24). (E) A01488, plaques staining with thioflavin S. (F) A01488, plaque staining with Aβ(1) affinity-purified antiserum specifically recognizing the NH2-terminus of Aβ. (G) A01488, plaque staining with Aβ(42) affinity-purified antiserum specifically recognizing the COOH-terminus of Aβ(1–42). (H) A01488, plaque staining with α40 affinitypurified antiserum specifically recognizing the COOH-terminus of Aβ(1–40). Magnifications: ×100 (A), ×250 (B), ×1000 (C, D, F, and G), ×640 (E), and ×500 (H).

Tables

  • Table 1.

    Concentrations of Aβ in transgenic and control mouse brains. Brain tissue was stained with monoclonal antibody (mAb) 4G8 (25), which recognizes both mouse and human Aβ. All amyloid deposits stained with 6E10 (24), which specifically recognizes human Aβ. No extracellular 6E10 staining was detected in three 105- to 106-day-old Tg+ mice or one 155-day-old Tg+ mouse (A01480, A01547, A01548, and Tg2576 founder). ++, 2 to 5 plaques per section; +++, 6 to 10 plaques per section; ++++, >10 plaques per section; -, no staining. Because all the pathological specimens were analyzed in a coded fashion, some nonspecific, equivocal staining that could not be blocked by preabsorption of the antibody with specific peptides was observed in some sections (indicated by ±).

    Mouse numberTransgeneAge when killed (days)Aβ(1–40) (pmol/g)Aβ(1–42/43) (pmol/g)Amyloid plaques
    Mice killed at 11 to 13 months of age
    A01484+361325219+++
    A01488+354192129++
    A01489 −354<2<2±
    A01492 −371<2<2 −
    A01493+368273177++++
    A01495 −354<2<2 −
    A01496 −354<2<2±
    Mean (±SEM) Aβ concentration in Tg+ mice:264 ± 38175 ± 26
    Mice killed at 6 to 8 months of age
    A01984 −233<2<2±
    A01987 −219<2<2 −
    A01989+2194518 −
    A02561 −214<2<2
    A02595 −207<2<2
    Mice killed at 2 to 5 months of age
    A02428 −139<2<2 −
    A02429 −139<2<2
    A02430 −139<2<2 −
    A02565+1187121
    A02900 −85<2<2
    A03103+67322
    A03107+674510
    Mean (±SEM) Aβ concentration in Tg+ mice:48 ± 813 ± 4