title: Vitamin C deficiency in the brain impairs cognition, increases amyloid accumulation and deposition, and oxidative stress in APP/PSEN1 and normally aging mice.
abstract: 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. These 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.
authors: †Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
authors: Shilpy
authors: S
authors: Dixit
authors: †Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
authors: Alexandra
authors: A
authors: Bernardo
authors: †Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
authors: Jennifer Michelle
authors: JM
authors: Walker
authors: †Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
authors: John Andrew
authors: JA
authors: Kennard
authors: †Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.|‡Program in Neuroscience, Vanderbilt University, Nashville, Tennessee 37232, United States.
authors: Grace Youngeun
authors: GY
authors: Kim
authors: †Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.|‡Program in Neuroscience, Vanderbilt University, Nashville, Tennessee 37232, United States.
authors: Eric Sean
authors: ES
authors: Kessler
authors: †Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
authors: Fiona Edith
authors: FE
authors: Harrison
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001007:Anxiety / Q000378:metabolism / Q000473:pathology; D001205:Ascorbic Acid / Q000378:metabolism; D001206:Ascorbic Acid Deficiency / Q000378:metabolism* / Q000473:pathology / Q000523:psychology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D003072:Cognition Disorders / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D007858:Learning / Q000502:physiology; D008297:Male; D008568:Memory / Q000502:physiology; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D060347:Sodium-Coupled Vitamin C Transporters / Q000235:genetics / Q000378:metabolism
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C555165:Slc23a2 protein, mouse; D060347:Sodium-Coupled Vitamin C Transporters; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D001205:Ascorbic Acid
keywords: Alzheimer’s disease; Vitamin C; amyloid; cognition; mouse models; oxidative stress
references: Arch Neurol. 2004 Jan;61(1):82-8
references: 14732624
references: J Nutr Health Aging. 2010 Jun;14(6):407-10
references: 20617280
references: Neurobiol Dis. 2009 Mar;33(3):482-98
references: 19130883
references: J Alzheimers Dis. 2002 Dec;4(6):517-22
references: 12629261
references: Neurology. 2000 Mar 28;54(6):1265-72
references: 10746596
references: Nutr Neurosci. 2009 Oct;12(5):203-18
references: 19761651
references: J Neurosci. 2009 Mar 18;29(11):3453-62
references: 19295151
references: Chem Senses. 2014 Jan;39(1):39-46
references: 24200528
references: Neuron. 2007 Sep 6;55(5):697-711
references: 17785178
references: Nat Med. 2002 May;8(5):514-7
references: 11984597
references: Behav Brain Res. 2014 May 1;264:34-42
references: 24508240
references: J Alzheimers Dis. 2009;16(1):93-8
references: 19158425
references: Cell Death Dis. 2014;5:e1083
references: 24577081
references: Nat Protoc. 2007;2(1):221-6
references: 17401357
references: Brain Res. 2010 Aug 12;1348:181-6
references: 20570663
references: Neurobiol Aging. 2007 Aug;28(8):1195-205
references: 16837103
references: Metab Brain Dis. 2009 Jun;24(2):271-82
references: 19296210
references: Epilepsia. 2011 Jan;52 Suppl 1:39-46
references: 21214538
references: J Alzheimers Dis. 2013;33(1):177-90
references: 22914588
references: JAMA. 2002 Jun 26;287(24):3230-7
references: 12076219
references: J Alzheimers Dis. 2011;26(1):7-18
references: 21558647
references: Front Aging Neurosci. 2010 Feb 09;2:3
references: 20552043
references: J Biol Chem. 2011 Aug 5;286(31):27559-72
references: 21642435
references: Ann N Y Acad Sci. 2002 Apr;959:275-84
references: 11976202
references: Am J Physiol Cell Physiol. 2009 Jul;297(1):C169-78
references: 19419995
references: J Neurochem. 2008 Aug;106(3):1198-208
references: 18466336
references: Neurosci Lett. 2005 Dec 23;390(2):87-92
references: 16169151
references: PLoS One. 2010;5(11):e14015
references: 21103342
references: Behav Brain Res. 2009 Mar 2;198(1):247-51
references: 18996418
references: J Comp Neurol. 2013 Apr 15;521(6):1322-33
references: 23047490
references: Brain Res. 2006 Jun 30;1097(1):52-8
references: 16725131
references: J Pharmacol Exp Ther. 2004 Nov;311(2):677-82
references: 15192085
references: Epilepsy Behav. 2013 Mar;26(3):343-51
references: 23321057
references: Behav Brain Res. 2013 May 15;245:120-7
references: 23419740
references: J Vis Exp. 2009;(23). pii: 949. doi: 10.3791/949
references: 19229182
references: J Med Assoc Thai. 2014 Apr;97(4):423-30
references: 24964685
references: J Neurosci. 2005 Oct 12;25(41):9367-77
references: 16221845
references: Free Radic Biol Med. 2010 Sep 1;49(5):821-9
references: 20541602
references: Neurochem Res. 2012 Dec;37(12):2706-14
references: 22878647
references: Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):841-6
references: 10639167
references: Epilepsy Res. 2015 Feb;110:20-5
references: 25616451
references: J Alzheimers Dis. 2004 Apr;6(2):171-5
references: 15096701
references: Arch Neurol. 2002 Jun;59(6):972-6
references: 12056933
references: Histochem Cell Biol. 2009 May;131(5):565-74
references: 19125272
references: Neurotoxicology. 2014 Sep;44:132-9
references: 24960222
references: Int J Geriatr Psychiatry. 1998 Nov;13(11):749-54
references: 9850871
references: J Neurochem. 2013 Feb;124(3):363-75
references: 23106783
references: Curr Opin Clin Nutr Metab Care. 2013 Jan;16(1):21-6
references: 23222705
references: BMJ. 1996 Mar 9;312(7031):608-11
references: 8595334
references: Alzheimer Dis Assoc Disord. 1998 Sep;12(3):121-6
references: 9772012
references: Nutr Neurosci. 2003 Jun;6(3):153-62
references: 12793519
references: Arch Neurol. 2012 Jul;69(7):836-41
references: 22431837
references: FASEB J. 2004 Feb;18(2):323-5
references: 14656990
references: Genes Brain Behav. 2007 Feb;6(1):54-65
references: 17233641
references: Nat Neurosci. 2012 Sep;15(9):1227-35
references: 22820466
references: Neurochem Int. 2009 Feb;54(2):111-8
references: 19041676
references: Genes Brain Behav. 2012 Apr;11(3):269-77
references: 22296218
references: Nat Protoc. 2006;1(6):3159-65
references: 17406579
references: Arch Neurol. 2009 Apr;66(4):435-40
references: 19204149
references: Proc Natl Acad Sci U S A. 1989 Aug;86(16):6377-81
references: 2762330
references: Behav Brain Res. 2009 Dec 28;205(2):550-8
references: 19703495
references: Neurology. 2012 Feb 7;78(6):387-95
references: 22302550
references: J Nutr Health Aging. 2004;8(2):99-107
references: 14978605
references: Free Radic Biol Med. 2001 Aug 1;31(3):345-54
references: 11461772
references: Neurobiol Dis. 2005 Apr;18(3):602-17
references: 15755686
references: Neurol Clin. 2000 Nov;18(4):829-46
references: 11072263
references: Free Radic Biol Med. 2009 Apr 15;46(8):965-88
references: 19439229
references: Neurosci Lett. 1998 Jul 24;251(2):105-8
references: 9718985
references: Arch Clin Neuropsychol. 2013 Aug;28(5):391-9
references: 23669447
references: Pharmacol Biochem Behav. 2009 Oct;93(4):443-50
references: 19539642
references: Neuron. 1997 Oct;19(4):939-45
references: 9354339