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Nutritional Neurosciences

Chronic Administration of Docosahexaenoic Acid Ameliorates the Impairment of Spatial Cognition Learning Ability in Amyloid ß–Infused Rats

Michio Hashimoto^*,1, Yoko Tanabe^*,, Yoshimi Fujii^*, Toshihiko Kikuta^**, Hitoshi Shibata^** and Osamu Shido^*

^* Department of Environmental Physiology, Center for Integrated Research in Science, Shimane University Faculty of Medicine, Izumo 693-8501, Japan and ^** Department of Life Science and Biotechnology, Shimane University of Faculty of Life and Environmental Science, Matsue 690-8504, Japan

¹To whom correspondence should be addressed. E-mail: michio1{at}med.shimane-u.ac.jp.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
We investigated whether administration of docosahexaenoic acid (DHA), a major (n-3) fatty acid of the brain, ameliorates the impairment of learning ability in an animal model of Alzheimer’s disease (AD), rats infused with amyloid-ß (Aß) peptide (1–40) into the cerebral ventricle. Inbred 3rd generation male rats (20 wk old) fed a fish oil–deficient diet were randomly divided into 4 groups: a vehicle group, an Aß peptide-infused group (Aß group), a DHA group, and an Aß + DHA group. A mini-osmotic pump filled with Aß peptide or vehicle was implanted in the rats, and they were tested for learning ability–related reference and working memory in an 8-arm radial maze. The rats were then orally fed DHA dissolved in 5% gum Arabic solution at 300 mg/(kg · d) (DHA and Aß + DHA groups) or vehicle alone (vehicle and Aß groups) and tested again for learning ability. DHA administered for 12 wk significantly reduced the increase in the number of reference and working memory errors in the Aß-infused rats, and increased both the cortico-hippocampal level of DHA and the molar ratio of DHA/arachidonic acid, suggesting an amelioration of the impaired spatial cognition learning ability. Furthermore, DHA suppressed the increases in the levels of lipid peroxide and reactive oxygen species in the cerebral cortex and the hippocampus of Aß-infused rats, suggesting that DHA increases antioxidative defenses. DHA is thus a possible therapeutic agent for ameliorating learning deficiencies due to Alzheimer’s disease.

KEY WORDS: • docosahexaenoic acid • therapeutic agent • spatial working memory • antioxidative defense • Alzheimer’s disease

Docosahexaenoic acid [DHA; 22:6(n-3)],² one of the main structural lipids in the mammalian brain, is essential for normal neurological development and for vision (1). Deficiency in this fatty acid is associated with a loss of discriminative learning ability (2,3); thus intake of DHA may restore lost learning ability. Consistent with these findings, we demonstrated that chronic administration of DHA enhances long-term memory in both young (4) and old (5) rats. Treatment with DHA improves the neurological condition in Zellweger’s syndrome, a peroxisomal disorder that produces serious mental retardation (6). More interestingly, the DHA level in the hippocampus was found to be very low (7) in patients with Alzheimer’s disease (AD), compared with that in brain samples from age-matched human controls. AD is characterized by the formation of neurofibrillary tangles and neuritic plaque of amyloid peptides such as amyloid-ß (Aß) peptide (1–40), as well as by neuronal and memory loss. We reported recently that preadministration of DHA protects against the impairment of learning ability in an animal model of AD, rats infused with Aß peptide (1–40) into the cerebral ventricle (8).

Epidemiologic studies show a relation between sources of dietary fish oil, especially DHA, and AD. Intake of DHA has been associated with reduced risk of AD (9). DHA oil supplementation was shown to improve intellectual function in the elderly (10). We therefore hypothesized that chronic administration of DHA may ameliorate the impairment of learning ability in Aß-infused rats.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
    Animals and diet. Wistar rats (generation 1, G1) (Jcl: Wistar; Clea Japan) were housed in a room under controlled temperature (23 ± 2°C), relative humidity (50 ± 10%), and light-dark cycles (light: 0800 to 2000 h; dark: 2000 to 0800 h). Rats consumed a fish oil–deficient diet (F-1®; Funabashi Farm) (Table 1) and water ad libitum. The inbred 3rd generation male rats [n = 38; 20 wk old; 376.3 ± 3.3 g body weight (BW)], fed the same F-1 diet, were randomly divided into 4 groups: a vehicle group (n = 9), an Aß peptide-infused group (Aß group) (n = 10), a DHA group (n = 9) and an Aß + DHA group (n = 10). The rats were handled and killed in accordance with the procedures outlined in the Guidelines for Animal Experimentation of Shimane Medical University, compiled from the Guidelines for Animal Experimentation of the Japanese Association for Laboratory Animal Science.

    Radial maze-learning ability and DHA administration. The rats were tested for learning ability 4 wk after the implantation of the mini-osmotic pump to verify the memory impairment. Learning-related behavior was assessed using an 8-arm radial maze (Toyo Sangyo) as described (4,5). Briefly, the rats were trained to acquire a reward (food-pellet) at the end of each of 4 arms of an 8-arm radial maze. The performance involved 2 parameters of memory function, i.e., reference memory error (RME), entry into unbaited arms; and working memory error (WME), repeated entry into arms that had already been visited and obtaining the rewards within a trial. Each rat was given 2 daily trials, 6 d/wk for a total of 2.5 wk. The DHA and Aß + DHA groups were then orally fed DHA-95E [300 mg/(kg · d), an ethyl-ester all-cis-4,7,10,13,16,19-docosahexaenoate with a purity of over 95%; Harima Chemicals] gently emulsified in a 5% gum Arabic solution in ice-cold water; the vehicle and Aß groups were fed an equal volume of vehicle only.

Seven weeks after starting the administration of DHA, the rats were tested again for learning ability using an 8-arm radial maze for a total of 5 wk, to assess the effect of DHA on the impairment of learning ability.

    Measurement of fatty acid profiles and oxidative status. After completing the behavioral studies, the rats were anesthetized with sodium pentobarbital (65 mg/kg BW, i.p.), blood was collected, and the cerebral cortex and hippocampus were separated as described (8). The tissues were stored at –80°C by flash-freezing in liquid N₂ until use or immediately homogenized in ice-cold 0.32 mol/L sucrose buffer (pH 7.4) containing 2 mmol/L EDTA, 0.5 mg/L leupeptin, 0.5 mg/L pepstatin, 0.5 mg/L aprotinin, and 0.2 mmol/L phenylmethylsulfonyl fluoride using a Polytron homogenizer (PCU 2–110; Kinematica). The homogenates were immediately subjected to the assays described below or stored at –80°C after liquid N₂ flash and bath until use.

Lipid peroxide concentration was assessed by the TBARS assay, as described (8,12). TBARS levels are expressed as nanomoles of malondialdehyde/mg protein. Malondialdehyde levels were calculated relative to a standard preparation of 1,1,3,3-tetraethoxypropane.

The levels of reactive oxygen species (ROS) were determined as described (8,12). Briefly, 50 µL freshly prepared tissue homogenate was mixed with 4.85 mL of 100 mmol/L potassium phosphate buffer (pH 7.4) and incubated with 2',7'-dichlorofluorescin diacetate in methanol at a final concentration of 5 µmol/L for 15 min at 37°C. The dye-loaded samples were centrifuged at 12,500 x g for 10 min at 4°C. The pellet was mixed on a vortex at 0°C in 5 mL of 100 mmol/L phosphate buffer (pH 7.4) and incubated again for 60 min at 37°C. Fluorescence was measured with a Hitachi 850 spectrofluorometer (Tokyo, Japan) at wavelengths of 488 nm for excitation and 525 nm for emission. The cuvette holder was maintained at 37°C. ROS were quantified from a dichlorofluorescin standard curve in methanol.

Fatty acid composition was determined by the one-step analysis of Lepage and Roy (13) by GC as described (12,14). Protein concentration was estimated by the method of Lowry et al. (15).

    Statistical analysis. Results are expressed as means ± SEM. Behavioral data were analyzed by a 2-factor (group and block) randomized block factorial ANOVA, and all other parameters were analyzed for intergroup differences by 1-way ANOVA. ANOVA was followed by Fisher’s PLSD for post-hoc comparisons. Correlation was determined by simple regression analysis. The statistical programs used were GB-STAT^TM 6.5.4 (Dynamic Microsystems), and StatView® 4.01 (MindVision Software, Abacus Concepts). Differences with P < 0.05 were considered significant.

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
    Body weight. Body weights did not differ among the groups after the administration of DHA for 12 wk (vehicle: 494 ± 8 g; DHA: 481 ± 6 g; Aß: 484 ± 9 g; Aß + DHA: 490 ± 10 g).

    Effect of DHA administration on radial-maze learning ability. The effects of Aß peptide (1–40) infused into the rat cerebral ventricle and that of DHA administered to vehicle and Aß-infused rats for 12 wk on reference and working memory-related learning ability are shown in Figures 1and 2, respectively. The score is expressed as the mean number of RMEs and WMEs for each group, with data averaged over blocks of 6 trials. The left panels in both figures indicate the effect of the infused Aß peptide (1–40). Randomized 2-factor (block and group) ANOVA to analyze the effect of the infused Aß revealed significant main effects of both blocks of trials (P < 0.0001) and groups (P < 0.0001) with a significant block x group interaction (P < 0.0001) on the number of RMEs (Fig. 1, left panel). Similarly, a significant main effect of blocks of trials (P < 0.0001) and groups (P < 0.0001) with a significant block x group interaction (P = 0.0174) was observed on the number of WMEs (Fig. 2, left panel). These results indicate that Aß peptide (1–40) infused into the rat cerebral ventricle impaired reference and working memory in the rats, suggesting learning impairment, a well-known characteristic of AD.

View larger version (20K): [in this window] [in a new window]   FIGURE 1 Effect of the infusion of amyloid ß (Aß) peptide (1–40) into the rat cerebral ventricle (left panel) and the effect of docosahexaenoic acid (DHA) administered to the Aß-infused rats (right panel) on reference memory–related learning ability in the radial maze task. Each value represents the number of RMEs as the mean ± SEM in each block of 6 trials. Groups without a common letter for the main effects of groups are significantly different at P < 0.05. Left panel: vehicle rats (n = 19), Aß rats (n = 19). The significance of differences between the 2 groups was determined by randomized 2-factor (block and group) ANOVA followed by Fisher’s PLSD test; main effects of blocks of trials and groups were both significant (P < 0.0001), with a significant block x group interaction (P < 0.0001) on the number of RMEs. Right panel: Aß rats (n = 9), Aß + DHA rats (n = 10), vehicle rats (n = 9), DHA (n = 10). The significance of differences among the 4 groups was determined by randomized 2-factor (block and group) ANOVA followed by Fisher’s PLSD test; main effects of blocks of trials and groups were both significant (P < 0.0001), with a significant block x group interaction (P < 0.0001) on the number of RME. Details of the subtest analysis between 2 groups of main effects of blocks of trials and groups, and between 2 groups of block x group interaction are shown in Table 2.

View larger version (21K): [in this window] [in a new window]   FIGURE 2 Effect of the infusion of Aß peptide (1–40) into the rat cerebral ventricle (left panel) and the effect of DHA administered to the Aß-infused rats (right panel) on working memory–related learning ability in the radial maze task. Each value represents the number of WMEs as the mean ± SEM in each block of 6 trials. Groups without a common letter for the main effects of groups are significantly different at P < 0.05. Left panel: vehicle rats (n = 19), Aß rats (n = 19). The significance of differences between 2 groups was determined by randomized 2-factor (block and group) ANOVA followed by Fisher’s PLSD test; significant main effects of blocks of trials (P < 0.0001) and groups (P < 0.0001) were observed, with a significant block x group interaction (P = 0.0174) on the number of WMEs. Right panel: Aß rats (n = 9), Aß + DHA rats (n = 10), vehicle rats (n = 9), vehicle + DHA (n = 10). The significance of differences among the 4 groups was determined by randomized 2-factor (block and group) ANOVA followed by Fisher’s PLSD test; the main effects of blocks of trial and groups were both significant (P < 0.0001), but without a significant block x group interaction (P = 0.0911) on the number of WMEs. Details of subtest analysis between 2 groups of main effects of blocks of trials and groups, and between 2 groups of block x group interaction are shown in Table 2.

    Effect of DHA administration on the oxidative status of rat brains. TBARS levels in both the cerebral cortex and the hippocampus were higher in the Aß group than in the vehicle, DHA, or Aß + DHA group (P < 0.05). Similarly, levels of ROS in both tissues were significantly higher in the Aß group than in any of the other groups (Table 5).

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

In the Aß-infused rats administered DHA, the increase in the level of DHA in the hippocampus and cerebral cortex was accompanied by a significant decrease in AA, resulting in a significant increase in the DHA/AA ratio. An increased DHA/AA ratio in the hippocampus is involved in the acquisition of higher reference memory–related learning ability. These observations are in agreement with the results of previous studies demonstrating that the DHA/AA ratio in the rat cortico-hippocampal region is inversely related to RMEs in radial maze tasks (4) and that an increased DHA/AA molar ratio in the cortico-hippocampal region of Aß-infused rats is associated with increased active avoidance response–related learning ability (8). The DHA/AA ratio in the cerebrum is an indicator of the antioxidative action of DHA in aged rats (16) and the increased cortico-hippocampal DHA/AA ratio in Aß-infused rats correlates negatively with corresponding levels of apoptotic products (8). Dietary DHA reduces the amount of AA in phospholipids by jointly decreasing its synthesis and simply replacing it physically (17). AA is considered to be an essential precursor of biologically active molecules, as well as a contributor to increased production of lipid peroxide through the cyclooxygenase pathway. This is because some of the AA-cascade products of endoperoxides themselves have free radical characteristics (18). DHA can modulate the inflammation and oxidative stress in which AA and its metabolites participate directly or indirectly (19). Thus, an increase in the DHA/AA ratio might contribute to decreased TBARS levels, because the higher the DHA level in the brain, the lower the AA level and the higher the DHA/AA ratio. An increased DHA/AA ratio in the cortico-hippocampal regions may therefore play an enhanced role against oxidative neuronal damage and impairment of learning and memory after the infusion of Aß.

The free-radical hypothesis of AD suggests that increased production of lipid peroxide causes deterioration of a wide variety of cellular enzymes, subsequently exacerbating the neurodegenerative processes (20). Chronic treatment with antioxidants, such as -tocopherol, improves cognitive functions in aging (21), a process frequently associated with increased oxidative damage and neurodegenerative diseases including AD. In the present study, DHA administration reduced the increased cortico-hippocampal TBARS and ROS levels in Aß rats to the levels in vehicle rats. DHA protects the brain against ischemic and excitotoxic damage in rats (22,23); it also acts as an antioxidant in brain tissue under certain circumstances because of the intrinsic potential of brain tissue to generate free radicals (16,24). Thus, DHA likely was more effective against Aß-induced oxidative stress at the neuronal level.

Epidemiologic studies show a relation between dietary (n-3) fatty acids and AD. High fish consumption, especially fish rich in n-3 fatty acid, is associated with a reduced risk for cognitive decline during aging and AD (9,25). Humans with senile dementia, treated for 6 mo with fish oil capsules (1400 mg DHA/d) in addition to established drugs, showed improvement in intellectual function (10,26). Although DHA was proposed to play a crucial role in the amelioration of learning impairment in AD, the mechanism of its activity in the brain is not clear. It is assumed, however, that DHA acts primarily as a structural fatty acid of the brain synaptic plasma membrane, resulting in alterations of neuronal functions (27,28). The infusion of Aß into the rat hippocampus evidently induces deficits in long-term potentiation (LTP) and in working memory (29). In addition, the acetylcholine level decreases in those experiencing memory impairment such as in AD (30). Dietary supplementation with DHA restores neurotransmitter release and reverses impairment in the expression of LTP (31). DHA is crucial for the induction of LTP, and DHA released endogenously during titanic stimulation is sufficient to trigger the expression of LTP (32). Dietary DHA increases cortical acetylcholine levels and concurrently improves avoidance performance (33); this was seen in rat hippocampus during aging (34–36). It improves radial maze-learning ability in aged rats (5,37) and increases the density of dendritic spines (37). These observations suggest that DHA-supplementation increases neuronal cell functions by being incorporated into neural membrane phospholipids.

We found recently that dietary DHA-induced increases in synaptic plasma membrane fluidity contribute to synaptic plasma membrane–bound functions that constitute avoidance learning–related memory (unpublished data). Reduced membrane fluidity correlates with diminished release of acetylcholine from the synaptosomes in vitro (38). Because Aß infusion into the rat brain reduces acetylcholine levels (30) and DHA administration prevents learning deficits (8), we speculate that presynaptic vesicular fusion and subsequent postsynaptic release of neurotransmitters is facilitated by DHA-induced increases in synaptic plasma membrane fluidity. These results suggest that dietary DHA, by being incorporated into neuronal membranes, affects cholinergic neurotransmission and subsequently exerts positive effects on behavior and brain function.

AD is an age-related disorder characterized by progressive cognitive decline and neurodegeneration (39). Senile plaques are composed predominantly of Aß peptide. The development of AD pathology was proposed to be the result of Aß deposition in association with membrane structure. It was demonstrated that plaque formation may be initiated in a plasma membrane form (40), suggesting that lipid composition in different compartments plays a role in Aß aggregation. Cholesterol modulates Aß-lipid interactions by decreasing the fluidity of the membrane bilayer and induces the aggregated formation of Aß (41). Aß entry into the membrane bilayer may result from an elevated cholesterol to phospholipid ratio. Chronic administration of DHA lowers the cholesterol to phospholipid molar ratio of the cerebral cortex synaptic plasma membrane in rats (42). In a mouse model of AD, a DHA-enriched diet produced a 40–50% reduction in the deposition of cortico-hippocampal Aß (43). Dietary supplementation with DHA can modulate the gene expression of many enzyme proteins involved in signal transduction processes (36,44). DHA administration stimulates the synthesis of transthyretin, a protein involved in the transport of thyroxin, suggesting that its administration to rats counteracts the formation of insoluble amyloid aggregates by stimulating the transcription of transthyretin. This protein also acts as an Aß-peptide scavenger, suggesting its role in preventing the formation of Aß aggregates (45). These data suggest that a DHA-enriched diet may prevent brain atrophy, senile plaque, and neurofibrillary tangle. Further studies are required to clarify the mechanisms of the DHA-mediated ameliorative effects on Alzheimer’s disease.

	ACKNOWLEDGMENTS

 
We thank Harima Chemicals (Tokyo, Japan) for the generous gift of DHA-95E as an ethyl ester derivative of all cis-4,7,10,13,16,19-docosahexaenoic acid.

	FOOTNOTES

 
² Abbreviations used: AA, arachidonic acid; Aß, amyloid-ß; AD, Alzheimer’s disease; BW, body weight; DHA, docosahexaenoic acid; DPA, docosapentaenoic acid; LTP, long-term potentiation; PLSD, protected least significant difference; RME, reference memory error; ROS, reactive oxygen species; USI, unsaturation index; WME, working memory error.

Manuscript received 8 September 2004. Initial review completed 12 October 2004. Revision accepted 18 November 2004.

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TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 

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