Memory-enhancing effects of secreted forms of the beta-amyloid precursor protein in normal and amnestic mice

Abstract

When administered intracerebroventricularly to mice performing various learning tasks involving either short-term or long-term memory, secreted forms of the beta-amyloid precursor protein (APPs751 and APPs695) have potent memory-enhancing effects and block learning deficits induced by scopolamine. The memory-enhancing effects of APPs were observed over a wide range of extremely low doses (0.05-5,000 pg intracerebroventricularly), blocked by anti-APPs antisera, and observed when APPs was administered either after the first training session in a visual discrimination or a lever-press learning task or before the acquisition trial in an object recognition task. APPs had no effect on motor performance or exploratory activity. APPs695 and APPs751 were equally effective in the object recognition task, suggesting that the memory-enhancing effect of APPs does not require the Kunitz protease inhibitor domain. These data suggest an important role for APPss on memory processes.

Figure 1

Administration of APP^s₇₅₁ results in a significant improvement of discrimination performance (a) and reduces learning deficits induced by scopolamine (b) in a go-no go visual discrimination task. APP^s₇₅₁ (0.05 to 5,000 pg) was administered i.c.v. to mice either alone or after s.c. treatment with scopolamine (3 mg/kg). See text for details. The discrimination ratios of the different groups evolved significantly [a: F(2, 54) = 119.01, P < 0.001; b: F(2, 70) = 50.72, P < 0.001] and differently [treatment x session interaction—a: F(10, 54) = 2.17, P < 0.03; b: F(10, 70) = 2.44, P < 0.01] across the three daily sessions. Empty, hatched, and filled bars represent the first, second, and third sessions, respectively. ∗, P < 0.05 and ∗∗, P < 0.01, vs. saline; #, P < 0.05 and ##, P < 0.01, vs. scopolamine, Dunnett’s two-tailed t test.

Figure 2

APP^s₇₅₁ significantly blocks retention deficits induced by scopolamine in the lever-press task. APP^s₇₅₁ (5 pg) was administered i.c.v. to mice either alone or after s.c. administration of scopolamine (3 mg/kg). See text for details. •, P < 0.05, vs. saline and #, P < 0.05, vs. scopolamine, Student-Newman-Keuls t test. (F ≥ 8.26, ∗, P < 0.02, ∗∗, P < 0.002, and ∗∗∗, P < 0.0001), within group analysis between the last 5 min of the acquisition session and the first 5 min of the retention session.

Figure 3

APP^s₇₅₁ and APP^s₆₉₅ improve retention performance and block retention deficits induced by scopolamine in an object recognition task. When using a 24-hr delay, both APP^s₇₅₁ and APP^s₆₉₅ (a and b, respectively) dose-dependently (0.05–5 pg) improve retention performance. When using a 3-hr delay, both APP^s₇₅₁ and APP^s₆₉₅ (c and d, respectively) block retention deficits induced by scopolamine (1 mg/kg). In each experiment, the recognition index significantly differed among groups [Kruskall-Wallis test: (a) H = 15.19, P < 0.01; (b) H = 29.96, P < 0.0001; (c) H = 34.39, P < 0.0001; (d) H = 37.52, P < 0.001]. ∗, P < 0.05, ∗∗, P < 0.01, and ∗∗∗, P < 0.001 vs. saline, and #, P < 0.05, ##, P < 0.01, and ###, P < 0.001 vs. scopolamine, Kolmogorov-Smirnov test.