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

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Abstract

Alzheimer's disease is a progressive and fatal neurodegenerative disease characterized by a build up of amyloid β (Aβ) 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. Aβ 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.

Introduction

Alzheimer's disease is the major cause of pre-senile dementia in the United States, with a prevalence of 5 million in 2008 (Alzheimer's Association, 2008). The main neuropathological features of Alzheimer's disease are a build up of amyloid β (Aβ) deposits, neurofibrillary tangles, elevated oxidative stress, and deterioration of the cholinergic system (Christen, 2000, Shah et al., 2008). Alzheimer's patients also have reduced plasma levels of vitamin C (ascorbic acid; ascorbate) (Charlton et al., 2004, Riviere et al., 1998) and high levels of dietary ascorbate or supplements have been suggested to lower the risk of developing the disease (Engelhart et al., 2002, Morris et al., 1998). Nevertheless, the mechanism of any protective role for ascorbate in the disease, and the relationship between ascorbate and cognition have yet to be elucidated.

Ascorbate levels in brain are generally much higher than in blood and other organs (Agus et al., 1997), and brain levels are tightly controlled. Although ascorbate is preferentially preserved in the brain relative to other organs, it is possible through dietary restriction to reduce ascorbate levels in mammals that cannot synthesize ascorbate (e.g. humans, guinea pigs, and Gulo−/− mice; Burk et al., 2006, Harrison et al., 2008, Hodges et al., 1971, Lykkesfeldt et al., 2007). It is more difficult to increase brain ascorbate above normal by dietary means. It has been shown that much higher levels of ascorbate can be obtained in plasma following intraperitoneal (i.p.) or intravenous (i.v.) administration than when administered by oral gavage (Chen et al., 2007). Improved cognition has been demonstrated following i.p. administration of ascorbate in mice and rats against age- and scopolamine-induced amnesia in a passive avoidance task, a memory test in the elevated plus maze, and a habituation test in light–dark activity chambers (de Angelis and Furlan, 1995, Parle and Dhingra, 2003, Shahidi et al., 2008) and in the water maze in rats treated with propionic acid which also reduced antioxidant capabilities (Pettenuzzo et al., 2002). Dietary ascorbate is vital for its antioxidant properties, which have long-term beneficial effects, whereas acutely administered ascorbate may have a greater impact on brain function in the short-term. The mechanism of action of ascorbate-induced improvement of memory is not yet known. However, it may be linked to neurotransmitter function. For example, ascorbate can attenuate the amnestic effects of the muscarinic antagonist scopolamine on memory and acetylcholinesterase (AChE) activity (de Angelis and Furlan, 1995, Lee et al., 2001, Parle and Dhingra, 2003). Much of the memory impairment in Alzheimer's disease is due to the degeneration of the basal forebrain cholinergic system, and acetylcholinesterase inhibitors are commonly used to treat the memory impairments resulting from Alzheimer's disease (Trinh et al., 2003).

The present experiment was conducted in middle-aged (12 months) and very old (24 months) APP/PSEN1 mice and wild-type controls. APP/PSEN1 mice manifest the Aβ deposits, elevated oxidative stress, and cognitive impairments found in Alzheimer's disease. APP/PSEN1 and wild-type mice were treated with ascorbate (i.p.) or the vehicle and tested in the Y-maze and Morris water maze. Following behavioral testing brain tissue was examined to investigate the effect of a short-term course of acute ascorbate treatments on ascorbate, oxidative stress, Aβ deposition and AChE activity.

Section snippets

Animals

APPSwe/PSEN1ΔE9 bigenic mice were obtained from Jackson Laboratory (Bar Harbor, ME, USA; stock no. 004462) and maintained as double hemizygotes by crossing with wild-type individuals on a B6C3F1/J background strain (Jackson Laboratories stock no. 100010). These mice carry two mutations associated with early onset or familial Alzheimer's disease and exhibit amyloid aggregation and amyloid-related neuropathology, elevated oxidative stress, age-dependent cholinergic dysfunction, and cognitive

Y-maze

There were no effects of age, genotype, or ascorbate treatment on the number of arm entries made during the 5-min Y-maze session [Fs < 2.57, Ps > .13]. Ascorbate treatment improved alternation rates in middle-aged and very old mice [F1, 25 = 11.401, P = .002, hp2 = .31, Fig. 1]. There was no effect of genotype nor any interactions among the factors [Fs < .580, Ps > .454]. Alternation rates were approximately 10% lower in very old mice than in middle-aged mice [F1, 25 = 7.945, P = .009, hp2 = .24].

Discussion

In the present study, acute parenteral treatment with ascorbate reversed some of the spatial learning and memory deficits found in APP/PSEN1 transgenic and aged wild-type mice. The ascorbate treatments had acute effects that were independent of long-term changes in lipid peroxidation, acetylcholinesterase activity or Alzheimer-type neuropathology in transgenic mice.

The administration of noötropic compounds has been shown to improve Y-maze spontaneous alternation performance following

Acknowledgements

This work was supported by grants from the National Institute of Health (AG023138 to James M May) and (AG022439 to Michael P McDonald).

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