Dataset Information

Dissociation between iron accumulation and ferritin upregulation in the aged substantia nigra: attenuation by dietary restriction.

ABSTRACT: Despite regulation, brain iron increases with aging and may enhance aging processes including neuroinflammation. Increases in magnetic resonance imaging transverse relaxation rates, R2 and R2*, in the brain have been observed during aging. We show R2 and R2* correlate well with iron content via direct correlation to semi-quantitative synchrotron-based X-ray fluorescence iron mapping, with age-associated R2 and R2* increases reflecting iron accumulation. Iron accumulation was concomitant with increased ferritin immunoreactivity in basal ganglia regions except in the substantia nigra (SN). The unexpected dissociation of iron accumulation from ferritin-upregulation in the SN suggests iron dyshomeostasis in the SN. Occurring alongside microgliosis and astrogliosis, iron dyshomeotasis may contribute to the particular vulnerability of the SN. Dietary restriction (DR) has long been touted to ameliorate brain aging and we show DR attenuated age-related in vivo R2 increases in the SN over ages 7 - 19 months, concomitant with normal iron-induction of ferritin expression and decreased microgliosis. Iron is known to induce microgliosis and conversely, microgliosis can induce iron accumulation, which of these may be the initial pathological aging event warrants further investigation. We suggest iron chelation therapies and anti-inflammatory treatments may be putative 'anti-brain aging' therapies and combining these strategies may be synergistic.

SUBMITTER: Walker T

PROVIDER: S-EPMC5115902 | biostudies-other | 2016 Oct

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Dissociation between iron accumulation and ferritin upregulation in the aged substantia nigra: attenuation by dietary restriction.

Walker Thomas T Michaelides Christos C Ekonomou Antigoni A Geraki Kalotina K Parkes Harold G HG Suessmilch Maria M Herlihy Amy H AH Crum William R WR So Po-Wah PW

Aging 20161001 10

Despite regulation, brain iron increases with aging and may enhance aging processes including neuroinflammation. Increases in magnetic resonance imaging transverse relaxation rates, R2 and R2*, in the brain have been observed during aging. We show R2 and R2* correlate well with iron content via direct correlation to semi-quantitative synchrotron-based X-ray fluorescence iron mapping, with age-associated R2 and R2* increases reflecting iron accumulation. Iron accumulation was concomitant with inc ...[more]

PMID: 27743512

Similar Datasets

Project description:Substantia nigra (SN) hyperechogenicity is present in most Parkinson's disease (PD) cases but is occasionally absent in some. To date, age, gender, disease severity, and other factors have been reported to be associated with SN hyperechogenicity in PD. Previous studies have discovered that excess iron deposition in the SN underlies its hyperechogenicity in PD, which may also indicate the involvement of genes associated with iron metabolism in hyperechogenicity. The objective of our study is to explore the potential associations between variants in iron metabolism-associated genes and SN echogenicity in Han Chinese PD. Demographic profiles, clinical data, SN echogenicity and genotypes were obtained from 221 Han Chinese PD individuals with a sufficient bone window. Serum ferritin levels were quantified in 92 of these individuals by immunochemical assay. We then compared factors between PD individuals with SN hyperechogenicity and those with SN hypoechogenicity to identify factors that predispose to SN hyperechogenicity. Of our 221 participants, 122 (55.2%) displayed SN hyperechogenicity, and 99 (44.8%) displayed SN hypoechogenicity. Gender and serum ferritin levels were found to be associated with SN hyperechogenicity. In total, 14 genes were included in the sequencing part. After data processing, 34 common single nucleotide polymorphisms were included in our further analyses. In our data, we also found a significantly higher frequency of PANK2 rs3737084 (genotype: OR = 2.07, P = 0.013; allele: OR = 2.51, P = 0.002) in the SN hyperechogenic group and a higher frequency of PLA2G6 rs731821 (genotype: OR = 0.45, P = 0.016; allele: OR = 0.44, P = 0.011) in the SN hypoechogenic group. However, neither of the two variants was found to be correlated with serum ferritin. This study demonstrated that genetic factors, serum ferritin level, and gender may explain the interindividual variability in SN echogenicity in PD. This is an explorative study, and further replication is warranted in larger samples and different populations.

Project description:We hypothesized that the study of gene expression at 1, 2, 4, 6 and 16 weeks in the substantia nigra (SN) after intrastriatal 6-OHDA in the Sprague-Dawley rat (rattus norvegicus) would identify cellular responses during the degenerative process that could be axoprotective. Specifically, we hypothesized that genes expressed within the SN that followed a profile of being highly upregulated early after the lesion (during active axonal degeneration) and then progressively declined to baseline over 16 weeks as DA neurons died are indicative of potential protective responses to the striatal 6-OHDA insult. Utilizing a ?-means cluster analysis strategy, we demonstrated that one such cluster followed this hypothesized expression pattern over time, and that this cluster contained several interrelated transcripts that are classified as regeneration-associated genes (RAGs) including Atf3, Sprr1a, Ecel1, Gadd45a, Gpnmb, Sox11, Mmp19, Srgap1, Rab15,Lifr, Trib3, Tgfb1, and Sema3c. All exemplar transcripts tested from this cluster (Sprr1a, Ecel1, Gadd45a, Atf3 and Sox11) were validated by qPCR and a smaller subset (Sprr1a, Gadd45a and Sox11) were shown to be exclusively localized to SN DA neurons using a dual label approach with RNAScope in situ hybridization and immunohistochemistry. Upregulation of RAGs is typically associated with the response to axonal injury in the peripheral nerves and was not previously reported as part of the axodegenerative process for DA neurons of the SN. Interestingly, as part of this cluster, other transcripts were identified based on their expression pattern but without a RAG provenance in the literature. These "RAG-like" transcripts need further characterization to determine if they possess similar functions to or interact with known RAG transcripts. Ultimately, it is hoped that some of the newly identified axodegeneration-reactive transcripts could be exploited as axoprotective therapies in PD and other neurodegenerative diseases.

Project description:α-Synuclein (α-syn) is a small presynaptic protein distributed ubiquitously in the central and peripheral nervous system. In normal conditions, α-syn is found in soluble form, while in Parkinson's disease (PD) it may phosphorylate, aggregate, and combine with other proteins to form Lewy bodies. The purpose of this study was to evaluate, in nonhuman primates, whether α-syn expression is affected by age and neurotoxin challenge. Young adult (n = 5, 5-10 years old) and aged (n = 4, 23-25 years old) rhesus monkeys received a single unilateral carotid artery injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Three months post-MPTP the animals were necropsied by transcardiac perfusion, and their brains extracted and processed with immunohistochemical methods. Quantification of tyrosine hydroxylase (TH)-positive substantia nigra (SN) neurons showed a significant 80-89% decrease in the side ipsilateral to MPTP administration in young and old animals. Optical density of TH- immunoreactivity (-ir) in the caudate and putamen presented a 60-70% loss compared with the contralateral side. α-Syn-ir was present in both ipsi- and contra- lateral MPTP-treated nigra, caudate, and putamen, mostly in fibers; its intracellular distribution was not affected by age. Comparison of α-syn-ir between MPTP-treated young and aged monkeys revealed significantly higher optical density for both the ipsi- and contralateral caudate and SN in the aged animals. TH and α-syn immunofluorescence confirmed the loss of nigral TH-ir dopaminergic neurons in the MPTP-treated side of intoxicated animals, but bilateral α-syn expression. Colabeling of GAD67 and α-syn immunofluorescence showed that α-syn expression was present mainly in GABAergic fibers. Our results demonstrate that, 3 months post unilateral intracarotid artery infusion of MPTP, α-syn expression in the SN is largely present in GABAergic fibers, regardless of age. Bilateral increase of α-syn expression in SN fibers of aged, compared with young rhesus monkeys, suggests that α-syn-ir may increase with age, but not after neurotoxin-induced dopaminergic nigral cell loss.

Dataset Information

Dissociation between iron accumulation and ferritin upregulation in the aged substantia nigra: attenuation by dietary restriction.

Publications

Dissociation between iron accumulation and ferritin upregulation in the aged substantia nigra: attenuation by dietary restriction.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets