Iron metabolism in diabetes-induced Alzheimer’s disease: a focus on insulin resistance in the brain

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Abstract

Alzheimer’s disease (AD) is characterized by an excessive accumulation of toxic amyloid beta (Aβ) plaques and memory dysfunction. The onset of AD is influenced by age, genetic background, and impaired glucose metabolism in the brain. Several studies have demonstrated that diabetes involving insulin resistance and glucose tolerance could lead to AD, ultimately resulting in cognitive dysfunction. Even though the relationship between diabetes and AD was indicated by significant evidences, the critical mechanisms and metabolic alterations in diabetes induced AD are not clear until now. Recently, iron metabolism has been shown to play multiple roles in the central nervous system (CNS). Iron deficiency and overload are associated with neurodegenerative diseases. Iron binds to Aβ and subsequently regulates Aβ toxicity in the CNS. In addition, previous studies have shown that iron is involved in the aggravation of insulin resistance. Considering these effects of iron metabolism in CNS, we expect that iron metabolism may play crucial roles in diabetic AD brain. Thus, we review the recent evidence regarding the relationship between diabetes-induced AD and iron metabolism.

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Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer's disease.

Robert D Bell, Berislav Zlokovic (2009)

Vascular dysfunction has a critical role in Alzheimer's disease (AD). Recent data from brain imaging studies in humans and animal models suggest that cerebrovascular dysfunction may precede cognitive decline and onset of neurodegenerative changes in AD and AD models. Cerebral hypoperfusion and impaired amyloid beta-peptide (Abeta) clearance across the blood-brain barrier (BBB) may contribute to the onset and progression of dementia AD type. Decreased cerebral blood flow (CBF) negatively affects the synthesis of proteins required for memory and learning, and may eventually lead to neuritic injury and neuronal death. Impaired clearance of Abeta from the brain by the cells of the neurovascular unit may lead to its accumulation on blood vessels and in brain parenchyma. The accumulation of Abeta on the cerebral blood vessels, known as cerebral amyloid angiopathy (CAA), is associated with cognitive decline and is one of the hallmarks of AD pathology. CAA can severely disrupt the integrity of the blood vessel wall resulting in micro or macro intracerebral bleedings that exacerbates neurodegenerative process and inflammatory response and may lead to hemorrhagic stroke, respectively. Here, we review the role of the neurovascular unit and molecular mechanisms in vascular cells behind AD and CAA pathogenesis. First, we discuss apparent vascular changes, including the cerebral hypoperfusion and vascular degeneration that contribute to different stages of the disease process in AD individuals. We next discuss the role of the low-density lipoprotein receptor related protein-1 (LRP), a key Abeta clearance receptor at the BBB and along the cerebrovascular system, whose expression is suppressed early in AD. We also discuss how brain-derived apolipoprotein E isoforms may influence Abeta clearance across the BBB. We then review the role of two interacting transcription factors, myocardin and serum response factor, in cerebral vascular cells in controlling CBF responses and LRP-mediated Abeta clearance. Finally, we discuss the role of microglia and perivascular macrophages in Abeta clearance from the brain. The data reviewed here support an essential role of neurovascular and BBB mechanisms in contributing to both, onset and progression of AD.

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Central obesity and increased risk of dementia more than three decades later.

R Whitmer, D Gustafson, E Barrett-Connor … (2008)

Numerous reports show that a centralized distribution of adiposity is a more dangerous risk factor for cardiovascular disease and diabetes than total body obesity. No studies have evaluated whether the same pattern exists with dementia. The objective was to evaluate the association between midlife central obesity and risk of dementia three decades later. A longitudinal analysis was conducted of 6,583 members of Kaiser Permanente of Northern California who had their sagittal abdominal diameter (SAD) measured in 1964 to 1973. Diagnoses of dementia were from medical records an average of 36 years later, January 1, 1994, to June 16, 2006. Cox proportional hazard models adjusted for age, sex, race, education, marital status, diabetes, hypertension, hyperlipidemia, stroke, heart disease, and medical utilization were conducted. A total of 1,049 participants (15.9%) were diagnosed with dementia. Compared with those in the lowest quintile of SAD, those in the highest had nearly a threefold increased risk of dementia (hazard ratio, 2.72; 95% CI, 2.33-3.33), and this was only mildly attenuated after adding body mass index (BMI) to the model (hazard ratio, 1.92; 95% CI, 1.58-2.35). Those with high SAD (>25 cm) and normal BMI had an increased risk (hazard ratio, 1.89; 95% CI, 0.98-3.81) vs those with low SAD ( 30 kg/m(2)) and with high SAD had the highest risk of dementia (HR, 3.60; 95% CI, 2.85-4.55). Central obesity in midlife increases risk of dementia independent of diabetes and cardiovascular comorbidities. Fifty percent of adults have central obesity; therefore, mechanisms linking central obesity to dementia need to be unveiled.

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Inflammation alters the expression of DMT1, FPN1 and hepcidin, and it causes iron accumulation in central nervous system cells.

Pamela J. Urrutia, Pabla Aguirre, Andrés Esparza … (2013)

Inflammation and iron accumulation are present in a variety of neurodegenerative diseases that include Alzheimer's disease and Parkinson's disease. The study of the putative association between inflammation and iron accumulation in central nervous system cells is relevant to understand the contribution of these processes to the progression of neuronal death. In this study, we analyzed the effects of the inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) and of lipopolysaccharide on total cell iron content and on the expression and abundance of the iron transporters divalent metal transporter 1 (DMT1) and Ferroportin 1 (FPN1) in neurons, astrocytes and microglia obtained from rat brain. Considering previous reports indicating that inflammatory stimuli induce the systemic synthesis of the master iron regulator hepcidin, we identified brain cells that produce hepcidin in response to inflammatory stimuli, as well as hepcidin-target cells. We found that inflammatory stimuli increased the expression of DMT1 in neurons, astrocytes, and microglia. Inflammatory stimuli also induced the expression of hepcidin in astrocytes and microglia, but not in neurons. Incubation with hepcidin decreased the expression of FPN1 in the three cell types. The net result of these changes was increased iron accumulation in neurons and microglia but not in astrocytes. The data presented here establish for the first time a causal association between inflammation and iron accumulation in brain cells, probably promoted by changes in DMT1 and FPN1 expression and mediated in part by hepcidin. This connection may potentially contribute to the progression of neurodegenerative diseases by enhancing iron-induced oxidative damage. © 2013 International Society for Neurochemistry.

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Author and article information

Contributors

Hyung-Seok Kim: +82-62-220-4090 , veritas@jnu.ac.kr

Juhyun Song:

ORCID: http://orcid.org/0000-0002-9165-8507

+82-61-379-2706 , juhyunsong@chonnam.ac.kr

Journal

Journal ID (nlm-ta): Biometals

Journal ID (iso-abbrev): Biometals

Title: Biometals

Publisher: Springer Netherlands (Dordrecht )

ISSN (Print): 0966-0844

ISSN (Electronic): 1572-8773

Publication date (Electronic): 24 July 2018

Publication date PMC-release: 24 July 2018

Publication date (Print): 2018

Volume: 31

Issue: 5

Pages: 705-714

Affiliations

[1 ]ISNI 0000 0000 9475 8840, GRID grid.254187.d, Department of Neurology, , Chosun University School of Medicine and Hospital, ; Gwangju, 61452 South Korea

[2 ]ISNI 0000 0001 0356 9399, GRID grid.14005.30, Department of Forensic Medicine, , Chonnam National University Medical School, ; Gwangju, 61469 South Korea

[3 ]ISNI 0000 0001 0356 9399, GRID grid.14005.30, Department of Anatomy, , Chonnam National University Medical School, ; Gwangju, 61469 South Korea

Author information

Juhyun Song http://orcid.org/0000-0002-9165-8507

Article

Publisher ID: 134

DOI: 10.1007/s10534-018-0134-2

PMC ID: 6133192

PubMed ID: 30043289

SO-VID: 64c67bf4-aad1-418e-bd66-1856921c9462

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 11 May 2018

Date accepted : 18 June 2018

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ScienceOpen disciplines: Biochemistry

Keywords: iron,diabetes,alzheimer’s disease (ad),amyloid beta (aβ),insulin resistance

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ScienceOpen disciplines: Biochemistry

Keywords: iron, diabetes, alzheimer’s disease (ad), amyloid beta (aβ), insulin resistance

Iron metabolism in diabetes-induced Alzheimer’s disease: a focus on insulin resistance in the brain

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Most cited references 103

Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer's disease.

Central obesity and increased risk of dementia more than three decades later.

Inflammation alters the expression of DMT1, FPN1 and hepcidin, and it causes iron accumulation in central nervous system cells.

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