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1.
Article in English | MEDLINE | ID: mdl-31546716

ABSTRACT

Manganese (Mn) is an essential trace element that is naturally found in the environment and is necessary as a cofactor for many enzymes and is important in several physiological processes that support development, growth, and neuronal function. However, overexposure to Mn may induce neurotoxicity and may contribute to the development of Alzheimer's disease (AD) and Parkinson's disease (PD). The present review aims to provide new insights into the involvement of Mn in the etiology of AD and PD. Here, we discuss the critical role of Mn in the etiology of these disorders and provide a summary of the proposed mechanisms underlying Mn-induced neurodegeneration. In addition, we review some new therapy options for AD and PD related to Mn overload.


Subject(s)
Alzheimer Disease/chemically induced , Manganese/toxicity , Neurotoxins/toxicity , Parkinson Disease/etiology , Animals , Humans , Mammals
2.
Sci Rep ; 8(1): 5600, 2018 04 04.
Article in English | MEDLINE | ID: mdl-29618789

ABSTRACT

Unrepaired DNA double-strand breaks (DSBs) are lethal. The present study compared the extent of DSBs, neuronal apoptosis, and status of two major DSB repair pathways - homologous combinational repair (HR) and nonhomologous end-joining (NHEJ) - in hippocampus of 5-6 month and 16-18 month-old wild-type and APP/PSEN1 mice fed control diet or high fat diet (60% fat from lard). We performed immunohistochemical staining and quantification for nuclear foci formation of γ-H2AX for DSBs, RAD51, and 53BP1, which represent the functional status of HR and NHEJ, respectively. Increased γ-H2AX and caspase-3 staining indicated greater DSBs and associated neuronal apoptosis in APP/PSEN1 mice at both ages studied. RAD51-positive foci were fewer in APP/PSEN1 indicating that HR processes may be diminished in these mice, although NHEJ (53BP1 staining) appeared unchanged. High fat diet in young wild-type mice led to similar changes to those observed in APP/PSEN1 mice (γ-H2AX and caspase-3 staining, and fewer RAD51-positive foci). Overall, these data suggest that APP/PSEN1- and high fat diet-associated early accumulation of DSBs and neuronal cell death, resulted at least in part, from inhibition of HR, one of the major DSB repair pathways.


Subject(s)
Alzheimer Disease/pathology , DNA Repair , Obesity/pathology , Alzheimer Disease/metabolism , Animals , Caspase 3/metabolism , DNA Breaks, Double-Stranded , Diet, High-Fat , Female , Genetic Loci , Hippocampus/metabolism , Histones/metabolism , Male , Mice , Mice, Inbred C57BL , Obesity/metabolism , Rad51 Recombinase/metabolism
3.
ACS Chem Neurosci ; 6(4): 570-81, 2015 Apr 15.
Article in English | MEDLINE | ID: mdl-25642732

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 Aß1-42 and a higher Aß1-42/1-40 ratio. By 14 months of age, oxidative stress levels were similar among groups, but there were more amyloid-ß 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.


Subject(s)
Aging/metabolism , Alzheimer Disease/metabolism , Ascorbic Acid Deficiency/metabolism , Brain/metabolism , Cognition Disorders/metabolism , Oxidative Stress/physiology , Aging/pathology , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Anxiety/metabolism , Anxiety/pathology , Ascorbic Acid/metabolism , Ascorbic Acid Deficiency/pathology , Ascorbic Acid Deficiency/psychology , Brain/pathology , Cognition Disorders/pathology , Disease Models, Animal , Female , Learning/physiology , Male , Memory/physiology , Mice, Transgenic , Motor Activity/physiology , Peptide Fragments/metabolism , Presenilin-1/genetics , Presenilin-1/metabolism , Sodium-Coupled Vitamin C Transporters/genetics , Sodium-Coupled Vitamin C Transporters/metabolism
4.
PLoS One ; 7(4): e35623, 2012.
Article in English | MEDLINE | ID: mdl-22558179

ABSTRACT

A new transgenic mouse model for global increases in the Sodium Dependent Vitamin C transporter 2 (SVCT2) has been generated. The SVCT2-Tg mouse shows increased SVCT2 mRNA levels in all organs tested and correspondingly increased ascorbic acid (ASC) levels in all organs except liver. The extent of the increase in transporter mRNA expression differed among mice and among organs. The increased ASC levels did not have any adverse effects on behavior in the SVCT2-Tg mice, which did not differ from wild-type mice on tests of locomotor activity, anxiety, sensorimotor or cognitive ability. High levels of SVCT2 and ASC were found in the kidneys of SVCT2-Tg mice and urinary albumin excretion was lower in these mice than in wild-types. No gross pathological changes were noted in kidneys from SVCT2-Tg mice. SVCT2 immunoreactivity was detected in both SVCT2 and wild-type mice, and a stronger signal was seen in tubules than in glomeruli. Six treatments with Paraquat (3x10 and 3x15 mg/kg i.p.) were used to induce oxidative stress in mice. SVCT2-Tg mice showed a clear attenuation of Paraquat-induced oxidative stress in lung, as measured by F(2)-isoprostanes. Paraquat also decreased SVCT2 mRNA signal in liver, lung and kidney in SVCT2-Tg mice.


Subject(s)
Ascorbic Acid/metabolism , Lung/metabolism , Mice, Transgenic/genetics , Paraquat/pharmacology , RNA, Messenger/biosynthesis , Sodium-Coupled Vitamin C Transporters/genetics , Albumins/metabolism , Animals , Anxiety/drug therapy , Anxiety/genetics , Cognition/drug effects , Cognition/physiology , F2-Isoprostanes/metabolism , Founder Effect , Kidney/drug effects , Kidney/metabolism , Liver/drug effects , Liver/metabolism , Lung/drug effects , Mice , Mice, Transgenic/metabolism , Models, Animal , Motor Activity/drug effects , Motor Activity/genetics , Organ Specificity , Oxidative Stress/drug effects , Sodium-Coupled Vitamin C Transporters/metabolism , Up-Regulation
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