Ascorbic acid attenuates scopolamine-induced spatial learning deficits in the water maze

This study assessed the extent to which high fat diet (HFD)-induced β-amyloid accumulation and cognitive decline in APP/PSEN1 mice are reversible through control of fat intake. Ten months of HFD (60% calories from fat) led to significant deficits in a 2-trial Y maze task, and nest building assay, and decreased voluntary locomotor activity. The HFD induced an inflammatory response, indicated by increased expression of several inflammatory markers. Substituting a low fat diet led to pronounced weight loss and correction of glucose intolerance, decreases in the inflammatory response, and improved performance on behavioral tasks in both wild-type and APP/PSEN1 transgenic mice. Insoluble β-amyloid levels, and extent of tau phosphorylation were also lower following dietary reversal in APP/PSEN1 mice compared to high fat-fed animals, indicating that the inflammatory response may have contributed to key pathogenic pathways in the Alzheimer’s disease model. The data suggest that weight loss can be a vital strategy for cognitive protection, but also highlight potential mechanisms for intervention when sustained weight loss is not possible.

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“…MDA was measured as thiobarbituric acid reactive substances as previously described (Harrison, et al, 2009). …”

Section: Methodsmentioning

confidence: 99%

Reversal of high fat diet-induced obesity improves glucose tolerance, inflammatory response, β-amyloid accumulation and cognitive decline in the APP/PSEN1 mouse model of Alzheimer's disease

Walker

Dixit

Saulsberry

et al. 2017

Neurobiology of Disease

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“…MDA was analyzed as thiobarbituric-reactive substances as described previously 65 . Values were calculated per milligram tissue wet weight.…”

Section: Methodsmentioning

confidence: 99%

Vitamin C Deficiency in the Brain Impairs Cognition, Increases Amyloid Accumulation and Deposition, and Oxidative Stress in APP/PSEN1 and Normally Aging Mice

Dixit

Bernardo

Walker

et al. 2015

ACS Chem. Neurosci.

110

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Subclinical vitamin C deficiency is widespread in many populations, but its role in both Alzheimer’s disease and normal aging is understudied. In the present study we decreased brain vitamin C in the APPSWE/PSEN1deltaE9 mouse model of Alzheimer’s disease, by crossing APP/PSEN1+ bigenic mice with SVCT2+/− heterozygous knockout mice, which have lower numbers of the sodium-dependent vitamin C transporter required for neuronal vitamin C transport. SVCT2+/− mice performed less well on the rotarod task at both 5 and 12 months of age compared to littermates. SVCT2+/− and APP/PSEN1+, mice, and the combination genotype SVCT2+/−APP/PSEN1+, were also impaired on multiple tests of cognitive ability (olfactory memory task, Y-maze alternation, conditioned fear, Morris water maze). In younger mice, both low vitamin C (SVCT2+/−) and APP/PSEN1 mutations increased brain cortex oxidative stress (malondialdehyde, protein carbonyls, F2-isoprostanes) and decreased total glutathione compared to wild-type controls. SVCT2+/− mice also had increased amounts of both soluble and insoluble Aβ1-42 and a higher Aβ1-42/1-40 ratio. By 14 months of age, oxidative stress levels were similar among groups, but there were more amyloid-β plaque deposits in both hippocampus and cortex of SVCT2+/−APP/PSEN1+ mice compared to APP/PSEN1+ mice with normal brain vitamin C. The data suggest that even moderate intracellular vitamin C deficiency plays an important role in accelerating amyloid pathogenesis, particularly during early stages of disease development, and that these effects are likely modulated by oxidative stress pathways.

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“…ROS are typically categorized as neurotoxic molecules and exert their detrimental effects via oxidation of essential molecules such as enzymes and cytoskeletal proteins (69,142,285). Excessive ROS also are associated with decreased performance in cognitive tasks in mammals (78,134,138,171,190,220,277,417), as well as invertebrates (125). During normal physiological aging, ROS production increases and antioxidant defenses decline; hence, ROS levels increase dramatically, resulting in neuronal oxidative stress (12,22,204,282,302,337).…”

mentioning

confidence: 99%

Reactive Oxygen Species in the Regulation of Synaptic Plasticity and Memory

Massaad

Klann

2011

Antioxidants & Redox Signaling

493

350

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The brain is a metabolically active organ exhibiting high oxygen consumption and robust production of reactive oxygen species (ROS). The large amounts of ROS are kept in check by an elaborate network of antioxidants, which sometimes fail and lead to neuronal oxidative stress. Thus, ROS are typically categorized as neurotoxic molecules and typically exert their detrimental effects via oxidation of essential macromolecules such as enzymes and cytoskeletal proteins. Most importantly, excessive ROS are associated with decreased performance in cognitive function. However, at physiological concentrations, ROS are involved in functional changes necessary for synaptic plasticity and hence, for normal cognitive function. The fine line of role reversal of ROS from good molecules to bad molecules is far from being fully understood. This review focuses on identifying the multiple sources of ROS in the mammalian nervous system and on presenting evidence for the critical and essential role of ROS in synaptic plasticity and memory. The review also shows that the inability to restrain either age-or pathology-related increases in ROS levels leads to opposite, detrimental effects that are involved in impairments in synaptic plasticity and memory function.

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Ascorbic acid attenuates scopolamine-induced spatial learning deficits in the water maze

Cited by 69 publications

References 55 publications

Reversal of high fat diet-induced obesity improves glucose tolerance, inflammatory response, β-amyloid accumulation and cognitive decline in the APP/PSEN1 mouse model of Alzheimer's disease

Reversal of high fat diet-induced obesity improves glucose tolerance, inflammatory response, β-amyloid accumulation and cognitive decline in the APP/PSEN1 mouse model of Alzheimer's disease

Vitamin C Deficiency in the Brain Impairs Cognition, Increases Amyloid Accumulation and Deposition, and Oxidative Stress in APP/PSEN1 and Normally Aging Mice

Reactive Oxygen Species in the Regulation of Synaptic Plasticity and Memory

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