Abstract
The liver-derived hormone hepcidin, a member of the defensin family of antimicrobial peptides, plays an important role in host defense and innate immunity due to its broad antibacterial and antiviral properties. Ferritin, an iron storage protein is often associated with iron deficiency, hypoferritinemia, hypoxia, and immune complications, which are all significant concerns for systemic infection in Alzheimer’s disease (AD) and Down’s syndrome (DS) dementia. Serum and post-mortem brain samples were collected from AD, DS and age-matched control subjects. Serum samples were analyzed with ELISA for ferritin, hepcidin and IL-6. Additionally, post-mortem brain sections were assessed by immunohistochemistry for iron-related and inflammatory proteins. A significant increase in serum hepcidin levels was found in DS, compared to controls and AD subjects (p < 0.0001). Hepcidin protein was visible in the epithelial cells of choroid plexus, meningeal macrophages and in the astrocytes close to the endothelium of blood vessels. Hepcidin co-localized with IL-6, indicating its anti-inflammatory properties. We found significant correlation between hypoferritinemia and elevated levels of serum hepcidin in AD and DS. Hepcidin can be transported via macrophages and the majority of the vesicular hepcidin enters the brain via a compromised blood brain barrier (BBB). Our findings provide further insight into the molecular implications of the altered iron metabolism in acute inflammation, and can aid towards the development of preventive strategies and novel treatments in the fight against neuroinflammation.
Highlights
Dementia is a global public health challenge for this generation, and the most prevalent cause of dementia is late onset of Alzheimer’s disease (LOAD), a fatal neurodegenerative disorder characterized by progressive cognitive and functional impairment associated with memory loss (Hardy et al, 1998)
We found that serum ferritin was significantly higher in aged controls compared to AD (p < 0.0001), whereas hepcidin levels were lower in AD (Figure 1E)
AD and Down’s syndrome (DS) subjects are likely to be both at a higher risk for SARS-COV-2 infection due to dis-balance in iron homeostasis and failure of amyloid protein clearance leading to neuro-inflammation
Summary
Dementia is a global public health challenge for this generation, and the most prevalent cause of dementia is late onset of Alzheimer’s disease (LOAD), a fatal neurodegenerative disorder characterized by progressive cognitive and functional impairment associated with memory loss (Hardy et al, 1998). The two primary pathological hallmarks of AD are senile plaques (SP), which are extracellular deposits of Aβ derived from the β-amyloid precursor protein (APP), and neurofibrillary tangles (NFTs), primarily composed of hyper-phosphorylated tau (Goedert et al, 1995; Hardy and Selkoe, 2002). Down’s syndrome (DS) is an aneuploidy due to triplication of all or part of chromosome 21, where the amyloid precursor protein (APP) gene is encoded, and plays a key role in the pathogenesis of AD dementia in DS (Wisniewski et al, 1985; Mann, 1988; Raha et al, 2013). In DS and in LOAD, neuroinflammation has been linked to both the exacerbation of SP and NFT pathology, as well as the clearance of Aβ from amyloid plaques (Bell et al, 2007; Mawuenyega et al, 2010; Wildsmith et al, 2013). The viruses and bacteria can activate glial cells and induce a pro-inflammatory state in the brain (Kanberg et al, 2020)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
