Sự suy giảm trí nhớ tương quan, sự gia tăng Aβ và các mảng amyloid ở chuột chuyển gen
Tóm tắt
Chuột chuyển gen quá biểu hiện isoform β-amyloid (Aβ) của protein tiền chất của người Alzheimer với 695 acid amin chứa đột biến Lys 670 → Asn, Met 671 → Leu có khả năng học tập và ghi nhớ bình thường trong các nhiệm vụ tham chiếu không gian và thay thế ở tuổi 3 tháng nhưng cho thấy sự suy giảm vào khoảng 9 đến 10 tháng tuổi. Sự gia tăng gấp năm lần nồng độ Aβ(1-40) và gấp 14 lần nồng độ Aβ(1-42/43) đi kèm với sự xuất hiện của những thiếu hụt hành vi này. Nhiều mảng Aβ có nhuộm đỏ Congo được phát hiện trong các cấu trúc vỏ não và limbic của chuột có lượng Aβ cao. Sự xuất hiện tương quan giữa các bất thường hành vi, sinh hóa và bệnh lý gợi nhớ đến bệnh Alzheimer ở những chú chuột chuyển gen này mở ra cơ hội mới để khám phá sinh lý bệnh và sinh học thần kinh của bệnh này.
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Tài liệu tham khảo
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The water maze was a circular pool (diameter 1 m) filled with water maintained at 29°C and made opaque by the addition of powdered milk. Mice were pretrained by swimming to a 12.7 cm by 12.7 cm Plexiglas platform that was submerged 1.5 cm beneath the surface of the water and placed at random locations within the pool. During pretraining heavy curtains were drawn around the pool so that mice were unfamiliar with the extramaze room cues on the first day of spatial training. Spatial training consisted of four trials per day each trial lasting until the mouse reached the platform or 60 s whichever came first. After each trial mice remained on the platform for 30 s. Twenty-four hours after the 12th and 24th trials all mice were subjected to a probe trial in which they swam for 60 s in the pool with the platform removed. Mice were monitored by a camera mounted in the ceiling directly above the pool and all trials were stored on videotape for subsequent analysis of platform crossings and percent time spent in each quadrant during probe trials. Visible-platform training—in the same pool but with a platform that was black slightly larger (14.2 cm by 14.2 cm) and raised above the surface of the water—was given at least 24 hours after the second probe trial. The platform location was varied randomly from trial to trial to eliminate the potentially confounding contribution of extramaze spatial cues. In both visible-platform and hidden-platform versions mice were placed in the pool facing toward the wall of the pool in one of seven randomly selected locations. The numbers of mice tested in the water maze were 12 transgenic and 12 controls at 2 months 13 transgenic and 14 controls at 6 months and 9 transgenic and 10 controls at 9 to 10 months of age.
The escape latency data were examined with a multifactor analysis of variance (ANOVA) including genotype (transgenic vs. control) age (2 months 6 months or 9 to 10 months) and training day (four trials per day). The ANOVA revealed significant main effects of genotype [F(1 384) = 65.19P < 0.0001] age [F(2 384) = 7.64P < 0.001] and trial block [F(5 384) =12.20P < 0.0001]. Moreover there was a significant interaction between genotype and age [F(2 384) = 10.13P < 0.0001] indicating that the transgene-induced impairment of escape latency increases with age.
All mice were also given a probe trial after 12 training trials (3 days at four trials per day). However neither the transgenic nor the control mice had learned to search selectively after only 12 trials. The early probe trial was necessary because of the possibility of transient differences manifested only early in training and because of the likelihood that we would have missed these differences because all behavioral tests were conducted blind to genotype. As none of the mice learned the task there were no differences among any groups; for the sake of clarity these data have not been presented graphically.
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We thank J. Loh A. Mariash J. Meiners W. Yunis H. B. Clark D. Borchelt G. Carlson and T. C. Saido for advice and technical help. Supported by NIH grants NS33249 (K.H.) AG9009 (G.C.) AG06656 (S.Y.) and AG12685 (S.Y.) NSF grant IBN9410131 (P.C.) the Alzheimer's Association (K.H. and S.Y.) the California State Department of Health (G.C.) the American Health Assistance Foundation (S.Y.) and the Neurosciences Education and Research Foundation (K.H.). Care of experimental animals described was in accordance with institutional guidelines.