Upregulation of Local Hepcidin Contributes to Iron Accumulation in Alzheimer's Disease Brains.

Autor:	Chaudhary S; Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA., Ashok A; Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA., McDonald D; Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA., Wise AS; Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA., Kritikos AE; Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA., Rana NA; Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA., Harding CV; Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA., Singh N; Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
Jazyk:	angličtina
Zdroj:	Journal of Alzheimer's disease : JAD [J Alzheimers Dis] 2021; Vol. 82 (4), pp. 1487-1497.
DOI:	10.3233/JAD-210221
Abstrakt:	Background: Accumulation of iron is a consistent feature of Alzheimer's disease (AD) brains. The underlying cause, however, remains debatable. Objective: To explore whether local hepcidin synthesized by brain cells contributes to iron accumulation in AD brains. Methods: Brain tissue from the cingulate cortex of 33 cases of AD pre-assigned to Braak stage I-VI, 6 cases of non-dementia, and 15 cases of non-AD dementia were analyzed for transcriptional upregulation of hepcidin by RT-qPCR and RT-PCR. Change in the expression of ferritin, ferroportin (Fpn), microglial activation marker Iba1, IL-6, and TGFβ2 was determined by western blotting. Total tissue iron was determined by colorimetry. Results: Significant transcriptional upregulation of hepcidin was observed in Braak stage III-VI relative to Braak stage I and II, non-AD dementia, and non-dementia samples. Ferritin was increased in Braak stage V, and a significant increase in tissue iron was evident in Braak stage III-VI. The expression of Iba1 and IL-6 was also increased in Braak stage III-VI relative to Braak stage I and II and non-AD dementia samples. Amyloid-β plaques were absent in most Braak stage I and II samples, and present in Braak stage III-VI samples with few exceptions. Conclusion: These observations suggest that upregulation of brain hepcidin is mediated by IL-6, a known transcriptional activator of hepcidin. The consequent downregulation of Fpn on neuronal and other cells results in accumulation of iron in AD brains. The increase in hepcidin is disease-specific, and increases with disease progression, implicating AD-specific pathology in the accumulation of iron.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu