Vitamin C reduces spatial learning deficits in middle-aged and very old APP/PSEN1 transgenic and wild-type mice

Abstract

Alzheimer's disease is a progressive and fatal neurodegenerative disease characterized by a build up of amyloid beta (Abeta) deposits, elevated oxidative stress, and deterioration of the cholinergic system. The present study investigated short-term cognitive-enhancing effects of acute intraperitoneal (i.p.) Vitamin C (ascorbate) treatment in APP/PSEN1 mice, a mouse model of Alzheimer's disease. Middle-aged (12 months) and very old (24 months) APP/PSEN1 bigenic and wild-type mice were treated with ascorbate (125 mg/kg i.p.) or the vehicle 1 h before testing on Y-maze spontaneous alternation and Morris water maze tasks. Very old mice performed more poorly on cognitive tasks than middle-aged mice. Ascorbate treatment improved Y-maze alternation rates and swim accuracy in the water maze in both wild-type and APP/PSEN1 mice. Abeta deposits and oxidative stress both increased with age, and acetylcholinesterase (AChE) activity was significantly reduced in APP/PSEN1 compared to wild-type mice. However, the short course of acute ascorbate treatment did not alter Alzheimer-like neuropathological features of plaque deposition, oxidative stress, or AChE activity. These data suggest that ascorbate may have noötropic functions when administered parenterally in high doses and that the mode of action is via an acute, pharmacological-like mechanism that likely modulates neurotransmitter function.

Figure 1. Ascorbate increases spontaneous alternation in middle-aged and very old APP/PSEN1 and Wild-type mice

Spatial working memory was tested in the Y-maze spontaneous alternation task. Middle-aged and Very old ascorbate-treated mice alternated more often than vehicle-treated age-matched mice and percent alternation was lower in Very old mice relative to Middle-age mice. There was no difference between wild-type (white bars) and APP/PSEN1 mice (black bars). Symbols: Ascorbate-treated vs. vehicle-treated mice * P<.05. Very old vs. Middle-aged mice +P<.01.

Figure 2. Ascorbate improves water maze performance in Middle-aged and Very old APP/PSEN1 and wild-type mice

Spatial reference memory was tested in the Morris water maze task. (a - d) All mice improved during the 10 days of water maze acquisition as shown by decreasing escape latencies (a & b) and search error (c & d). Both escape latencies and search error were greater in Very old mice compared to Middle-aged mice during water maze acquisition. Ascorbate treatment did not affect water maze acquisition. In the water maze probe trial (e-g) memory was assessed by time spent within target and non-target quadrants (e & f) and search error (g). (e) All Middle-aged mice demonstrated memory for the platform location, spending more time swimming in the platform quadrant than non-platform quadrants. In contrast, (f) spatial memory was impaired in vehicle-treated Very old APP/PSEN1 mice, as indicated by random swimming random during the probe trial. (g) Ascorbate-treated Middle-aged mice had lower search error than vehicle-treated controls, indicating better memory for the platform location. The same pattern was not observed in Very old mice. Ascorbate treatments reversed this impairment in the Very old transgenics. Symbols: Ascorbate-treated vs. vehicle-treated mice * P<0.05. Target vs. non-target swim time ^# P<.05.

Figure 3. Ascorbate, oxidative stress and amyloid deposits increase with age

Relative to Middle-aged mice, Very old mice had (a) higher ascorbate levels in cortex, liver and serum, and (b) increased malondialdehyde levels in the cortex. Neither genotype nor treatment affected ascorbate or malondialdehyde levels. (c) Aβ plaque deposits increased in the cortex with age but were unaffected by treatment. (d) AChE activity was significantly lower in APP/PSEN1 mice than wild-type mice but did not vary significantly according to treatment or age. Data shown are collapsed across treatment group. Symbols: Very old vs. Middle-aged mice ⁺⁺⁺ P<0.001; APP/PSEN1 vs. wild-type mice ** P<0.01.

Figure 4. Very old APP/PS1 mice exhibit increased levels of Aβ deposits compared with Middle-aged APP/PS1 mice

Representative images of Thioflavin-S staining in hippocampus and overlying cortex in (a) Middle-aged and (b) Very old APP/PS1 mice. Images shown reflect the median percent plaque coverage for each age group.