Dysregulation of Neuronal Iron Homeostasis as an Alternative Unifying Effect of Mutations Causing Familial Alzheimer's Disease

Frontiers in Neuroscience
Amanda L LumsdenMichael Lardelli

Abstract

The overwhelming majority of dominant mutations causing early onset familial Alzheimer's disease (EOfAD) occur in only three genes, PSEN1, PSEN2, and APP. An effect-in-common of these mutations is alteration of production of the APP-derived peptide, amyloid β (Aβ). It is this key fact that underlies the authority of the Amyloid Hypothesis that has informed Alzheimer's disease research for over two decades. Any challenge to this authority must offer an alternative explanation for the relationship between the PSEN genes and APP. In this paper, we explore one possible alternative relationship - the dysregulation of cellular iron homeostasis as a common effect of EOfAD mutations in these genes. This idea is attractive since it provides clear connections between EOfAD mutations and major characteristics of Alzheimer's disease such as dysfunctional mitochondria, vascular risk factors/hypoxia, energy metabolism, and inflammation. We combine our ideas with observations by others to describe a "Stress Threshold Change of State" model of Alzheimer's disease that may begin to explain the existence of both EOfAD and late onset sporadic (LOsAD) forms of the disease. Directing research to investigate the role of dysregulation of iron homeost...Continue Reading

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Citations

Jan 13, 2019·Annals of Neurology·Francesco PanzaBruno P Imbimbo
Jan 25, 2020·International Journal of Molecular Sciences·Pi-Shan SungKuen-Jer Tsai
May 22, 2019·Expert Review of Neurotherapeutics·Francesco PanzaBruno Pietro Imbimbo
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Jan 6, 2021·Communications Biology·Rodrigo CataldiMichele Vendruscolo
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Aug 14, 2021·Trends in Biochemical Sciences·Francesca RizzolloPatrizia Agostinis

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Methods Mentioned

BETA
X-ray
fluorescence spectroscopy
gene-trap
protein folding

Software Mentioned

EOfAD

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