%0 Journal Article %J J Alzheimers Dis %D 2016 %T Iron Regulates Apolipoprotein E Expression and Secretion in Neurons and Astrocytes. %A Xu, He %A Perreau, Victoria M %A Dent, Krista A %A Bush, Ashley I %A Finkelstein, David I %A Adlard, Paul A %K Amyloid beta-Peptides %K Animals %K Apolipoproteins E %K Astrocytes %K Blotting, Western %K Cell Survival %K Cells, Cultured %K Cerebral Cortex %K Copper %K Ferritins %K Immunohistochemistry %K Iron %K Mice, Inbred C57BL %K Neurons %K Polymerase Chain Reaction %K Reactive Oxygen Species %K Receptors, LDL %K RNA, Messenger %K Tumor Suppressor Proteins %K Zinc %X

BACKGROUND: There is strong evidence that iron homeostasis is impaired in the aging and Alzheimer's disease (AD) brain and that this contributes to neurodegeneration. Apolipoprotein E (APOE) has been identified as the strongest genetic risk factor for AD. However, the interaction between the two has yet to be fully explored.

OBJECTIVE: This study aimed to investigate the relationship between exogenous iron levels and ApoE in neurons and astrocytes.

METHODS: Our study used primary cultured cortical neurons and astrocytes to investigate the changes in ApoE caused by iron. Western blot and RT-PCR were used to measure ApoE.

RESULTS: We observed that iron upregulated intracellular ApoE levels in both neurons and astrocytes at the post-transcriptional and transcriptional level, respectively. However, there was less full-length ApoE secreted by neurons and astrocytes after iron treatment. We speculate that this might impair brain lipid metabolism and amyloid-β clearance. In terms of ApoE receptors, we observed that neuronal LRP-1 levels were increased by the addition of exogenous iron, which could contribute to AβPP endocytosis in neurons. However, there were no significant changes in neuronal LDLR, astrocyte LDLR, or astrocyte LRP-1.

CONCLUSION: Our study reveals that iron may contribute to the pathogenesis of AD by affecting ApoE and its receptors and supports the notion that iron chelation should be investigated as a therapeutic strategy for AD.

%B J Alzheimers Dis %V 51 %P 471-87 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890748?dopt=Abstract %R 10.3233/JAD-150797 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Overexpression of Metallothionein-1 Modulates the Phenotype of the Tg2576 Mouse Model of Alzheimer's Disease. %A Manso, Yasmina %A Comes, Gemma %A López-Ramos, Juan C %A Belfiore, Mónica %A Molinero, Amalia %A Giralt, Mercedes %A Carrasco, Javier %A Adlard, Paul A %A Bush, Ashley I %A Delgado-García, José María %A Hidalgo, Juan %K Age Factors %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Animals %K Anxiety %K Disease Models, Animal %K Exploratory Behavior %K Female %K Gene Expression Regulation %K Humans %K Male %K Matrix Metalloproteinase 16 %K Maze Learning %K Metallothionein %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Motor Activity %K Mutation %K Phenotype %K Psychomotor Disorders %X

Alzheimer's disease (AD) is the most commonly diagnosed dementia, where signs of neuroinflammation and oxidative stress are prominent. In this study we intend to further characterize the roles of the antioxidant, anti-inflammatory, and heavy metal binding protein, metallothionein-1 (MT-1), by crossing Mt1 overexpressing mice with a well-known mouse model of AD, Tg2576 mice, which express the human amyloid-β protein precursor (hAβPP) with the Swedish K670N/M671L mutations. Mt1 overexpression increased overall perinatal survival, but did not affect significantly hAβPP-induced mortality and weight loss in adult mice. Amyloid plaque burden in ∼14-month-old mice was increased by Mt1 overexpression in the hippocampus but not the cortex. Despite full length hAβPP levels and amyloid plaques being increased by Mt1 overexpression in the hippocampus of both sexes, oligomeric and monomeric forms of Aβ, which may contribute more to toxicity, were decreased in the hippocampus of females and increased in males. Several behavioral traits such as exploration, anxiety, and learning were altered in Tg2576 mice to various degrees depending on the age and the sex. Mt1 overexpression ameliorated the effects of hAβPP on exploration in young females, and potentiated those on anxiety in old males, and seemed to improve the rate of spatial learning (Morris water maze) and the learning elicited by a classical conditioning procedure (eye-blink test). These results clearly suggest that MT-1 may be involved in AD pathogenesis.

%B J Alzheimers Dis %V 51 %P 81-95 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836194?dopt=Abstract %R 10.3233/JAD-151025