. Dysregulation of Neuronal Iron Homeostasis as an Alternative Unifying Effect of Mutations Causing Familial Alzheimer's Disease. Front Neurosci. 2018;12:533. Epub 2018 Aug 13 PubMed.

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  1. This is a well-thought-out hypothesis paper. It presents us with a new intellectual framework for future studies of the role of familial Alzheimer’s disease mutations in the amyloid precursor protein (APP) and presenilin genes to change iron, metal, and oxidative homeostasis in neurons. 

    Previously, the scientific and medical communities had been completely focused, for good reason, on the capacity of key familial AD mutations to act to change the cleavage rate of the APP protein to generate amyloid. It should be noted, however, that amyloidosis is not present in all patients with AD-like cognitive change and that papers in excellent journals since 2000, along with other recent publications (Venkataramani et al., 2018; Belaidi et al., 2018) support APP’s role in oxidative iron homeostasis. This present publication gives impetus for future studies of APP's biological function in iron/metal homeostasis, for example, in children and adults long before the onset of amyloidosis and senility.

    References:

    . Manganese causes neurotoxic iron accumulation via translational repression of Amyloid Precursor Protein (APP) and H-Ferritin. J Neurochem. 2018 Aug 27; PubMed.

    . Marked Age-Related Changes in Brain Iron Homeostasis in Amyloid Protein Precursor Knockout Mice. Neurotherapeutics. 2018 Aug 15; PubMed.

  2. To iron out a few kinks in Alzheimer’s disease field, Lumsden et al. have built an iron framework that might unite, functionally, several known mutations associated with the familial form of AD. It is timely and thought provoking.

    The “traditional” approach to understanding AD has been a frontal assault upon the most prominent pathological accretion constituents: Amyloid-β peptide (Aβ) and microtubule-associated protein tau. This is, of course, a reasonable first approach, based on the presumption that AD’s root causes can be seen by examining its most typical neuropathological symptoms. However, while Aβ plaques and tau tangles are both neurotoxic, whether they are root causes or exacerbating results of the actual causes of AD remains to be demonstrated. Understanding non-disease functions of the Aβ-precursor protein (APP) and tau protein may prove useful to tracing dysfunctions that lead to AD. Leaving aside tau for the moment, Lumsden and colleagues have provided a strong theoretical framework that functionally unifies several known autosomal-dominant mutations associated with rare familial forms of AD (FAD). Specifically, they note that disruption of iron (Fe) cellular homeostasis (FeCH) is a trait shared by multiple FAD mutations.

    It is always tempting to restrict understanding of a gene product to its earliest circumstance of discovery. Our understanding of APP and other “AD-associated” proteins, such as the presenilins (PSEN), which happen to take part in APP processing in both its amyloidogenic and non-amyloidogenic pathways, is now progressing beyond the initial discovery stage. In this context, the authors illustrate how PSENs and APP also are important actors in FeCH, and disruption of the FeCH functions may be a key step in AD pathogenesis.

    Notably, it is not only FeCH disruption that could be a vital, mechanistic explanation for AD, but that at least some of the same molecular actors also participate in broader metal ion homeostasis, including for Mn, and they can be perturbed by metallic toxins, such as Pb. Furthermore, there may be critical junctures in APP’s participation in FeCH, such as a proposed nexus on the APP 5’-UTR that includes overlapping iron response element (IRE), IL-1 acute box, and even specific microRNA binding sites. This IRE’s Fe-related regulation is achieved through binding with iron regulatory protein 1 (IRP1). However, the IRP1-APP IRE interaction could also be altered by Cu (Oshiro et al., 2002; Rogers et al., 2002), Pb, and Mn (Venkataramani et al., 2018). 

    In synopsis, the solidly-supported theoretical framework in the review certainly provides a direction to investigate early functional disruption of APP that could appear long before any detectable classic neuropathology or behavioral symptoms (such as MCI) could be noticed.

    References:

    . Modulation of iron regulatory protein-1 by various metals. Biochem Biophys Res Commun. 2002 Jan 11;290(1):213-8. PubMed.

    . An iron-responsive element type II in the 5'-untranslated region of the Alzheimer's amyloid precursor protein transcript. J Biol Chem. 2002 Nov 22;277(47):45518-28. Epub 2002 Aug 26 PubMed.

    . Manganese causes neurotoxic iron accumulation via translational repression of Amyloid Precursor Protein (APP) and H-Ferritin. J Neurochem. 2018 Aug 27; PubMed.

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