Interplay of Ferritin Accumulation and Ferroportin Loss in Ageing Brain: Implication for Protein Aggregation in Down Syndrome Dementia, Alzheimer’s, and Parkinson’s Diseases
Iron accumulates in the ageing brain and in brains with neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Down syndrome (DS) dementia. However, the mechanisms of iron deposition and regional selectivity in the brain are ill-understo...
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MDPI AG
2022-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/3/1060 |
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| author | Animesh Alexander Raha Anwesha Biswas James Henderson Subhojit Chakraborty Anthony Holland Robert P. Friedland Elizabeta Mukaetova-Ladinska Shahid Zaman Ruma Raha-Chowdhury |
| author_facet | Animesh Alexander Raha Anwesha Biswas James Henderson Subhojit Chakraborty Anthony Holland Robert P. Friedland Elizabeta Mukaetova-Ladinska Shahid Zaman Ruma Raha-Chowdhury |
| author_sort | Animesh Alexander Raha |
| collection | DOAJ |
| description | Iron accumulates in the ageing brain and in brains with neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Down syndrome (DS) dementia. However, the mechanisms of iron deposition and regional selectivity in the brain are ill-understood. The identification of several proteins that are involved in iron homeostasis, transport, and regulation suggests avenues to explore their function in neurodegenerative diseases. To uncover the molecular mechanisms underlying this association, we investigated the distribution and expression of these key iron proteins in brain tissues of patients with AD, DS, PD, and compared them with age-matched controls. Ferritin is an iron storage protein that is deposited in senile plaques in the AD and DS brain, as well as in neuromelanin-containing neurons in the Lewy bodies in PD brain. The transporter of ferrous iron, Divalent metal protein 1 (DMT1), was observed solely in the capillary endothelium and in astrocytes close to the ventricles with unchanged expression in PD. The principal iron transporter, ferroportin, is strikingly reduced in the AD brain compared to age-matched controls. Extensive blood vessel damage in the basal ganglia and deposition of punctate ferritin heavy chain (FTH) and hepcidin were found in the caudate and putamen within striosomes/matrix in both PD and DS brains. We suggest that downregulation of ferroportin could be a key reason for iron mismanagement through disruption of cellular entry and exit pathways of the endothelium. Membrane damage and subsequent impairment of ferroportin and hepcidin causes oxidative stress that contributes to neurodegeneration seen in DS, AD, and in PD subjects. We further propose that a lack of ferritin contributes to neurodegeneration as a consequence of failure to export toxic metals from the cortex in AD/DS and from the substantia nigra and caudate/putamen in PD brain. |
| first_indexed | 2024-03-09T23:50:30Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T23:50:30Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-47dcda057fc341f68062688ecfacae7e2023-11-23T16:34:19ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-01-01233106010.3390/ijms23031060Interplay of Ferritin Accumulation and Ferroportin Loss in Ageing Brain: Implication for Protein Aggregation in Down Syndrome Dementia, Alzheimer’s, and Parkinson’s DiseasesAnimesh Alexander Raha0Anwesha Biswas1James Henderson2Subhojit Chakraborty3Anthony Holland4Robert P. Friedland5Elizabeta Mukaetova-Ladinska6Shahid Zaman7Ruma Raha-Chowdhury8John van Geest Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge CB2 2PY, UKDepartment of Biochemistry, The M. S. University of Baroda, Vadodara 39002, IndiaJohn van Geest Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge CB2 2PY, UKJohn van Geest Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge CB2 2PY, UKCambridge Intellectual & Developmental Disabilities Research Group, Department of Psychiatry, University of Cambridge, Cambridge CB2 8AH, UKDepartment of Neurology, School of Medicine University of Louisville, Louisville, KY 40292, USADepartment of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester LE1 7RH, UKCambridge Intellectual & Developmental Disabilities Research Group, Department of Psychiatry, University of Cambridge, Cambridge CB2 8AH, UKJohn van Geest Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge CB2 2PY, UKIron accumulates in the ageing brain and in brains with neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Down syndrome (DS) dementia. However, the mechanisms of iron deposition and regional selectivity in the brain are ill-understood. The identification of several proteins that are involved in iron homeostasis, transport, and regulation suggests avenues to explore their function in neurodegenerative diseases. To uncover the molecular mechanisms underlying this association, we investigated the distribution and expression of these key iron proteins in brain tissues of patients with AD, DS, PD, and compared them with age-matched controls. Ferritin is an iron storage protein that is deposited in senile plaques in the AD and DS brain, as well as in neuromelanin-containing neurons in the Lewy bodies in PD brain. The transporter of ferrous iron, Divalent metal protein 1 (DMT1), was observed solely in the capillary endothelium and in astrocytes close to the ventricles with unchanged expression in PD. The principal iron transporter, ferroportin, is strikingly reduced in the AD brain compared to age-matched controls. Extensive blood vessel damage in the basal ganglia and deposition of punctate ferritin heavy chain (FTH) and hepcidin were found in the caudate and putamen within striosomes/matrix in both PD and DS brains. We suggest that downregulation of ferroportin could be a key reason for iron mismanagement through disruption of cellular entry and exit pathways of the endothelium. Membrane damage and subsequent impairment of ferroportin and hepcidin causes oxidative stress that contributes to neurodegeneration seen in DS, AD, and in PD subjects. We further propose that a lack of ferritin contributes to neurodegeneration as a consequence of failure to export toxic metals from the cortex in AD/DS and from the substantia nigra and caudate/putamen in PD brain.https://www.mdpi.com/1422-0067/23/3/1060basal ganglialocus coeruleussubstantia nigrastriosomes/matrixneurodegenerationferritin |
| spellingShingle | Animesh Alexander Raha Anwesha Biswas James Henderson Subhojit Chakraborty Anthony Holland Robert P. Friedland Elizabeta Mukaetova-Ladinska Shahid Zaman Ruma Raha-Chowdhury Interplay of Ferritin Accumulation and Ferroportin Loss in Ageing Brain: Implication for Protein Aggregation in Down Syndrome Dementia, Alzheimer’s, and Parkinson’s Diseases International Journal of Molecular Sciences basal ganglia locus coeruleus substantia nigra striosomes/matrix neurodegeneration ferritin |
| title | Interplay of Ferritin Accumulation and Ferroportin Loss in Ageing Brain: Implication for Protein Aggregation in Down Syndrome Dementia, Alzheimer’s, and Parkinson’s Diseases |
| title_full | Interplay of Ferritin Accumulation and Ferroportin Loss in Ageing Brain: Implication for Protein Aggregation in Down Syndrome Dementia, Alzheimer’s, and Parkinson’s Diseases |
| title_fullStr | Interplay of Ferritin Accumulation and Ferroportin Loss in Ageing Brain: Implication for Protein Aggregation in Down Syndrome Dementia, Alzheimer’s, and Parkinson’s Diseases |
| title_full_unstemmed | Interplay of Ferritin Accumulation and Ferroportin Loss in Ageing Brain: Implication for Protein Aggregation in Down Syndrome Dementia, Alzheimer’s, and Parkinson’s Diseases |
| title_short | Interplay of Ferritin Accumulation and Ferroportin Loss in Ageing Brain: Implication for Protein Aggregation in Down Syndrome Dementia, Alzheimer’s, and Parkinson’s Diseases |
| title_sort | interplay of ferritin accumulation and ferroportin loss in ageing brain implication for protein aggregation in down syndrome dementia alzheimer s and parkinson s diseases |
| topic | basal ganglia locus coeruleus substantia nigra striosomes/matrix neurodegeneration ferritin |
| url | https://www.mdpi.com/1422-0067/23/3/1060 |
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