. Iron Responsive Element-Mediated Responses to Iron Dyshomeostasis in Alzheimer's Disease. J Alzheimers Dis. 2021 Oct 25; PubMed.

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  1. This paper makes a number of unexpected and elegant observations that support an important role of iron dyshomeostasis in Alzheimer’s disease. Of the more than 10,000 gene sets they analyzed, the authors found the “Blalock Alzheimer’s Disease Up” gene set to be the most highly enriched for genes with mRNAs containing iron responsive elements (IREs) in their untranslated regions. Gene transcripts with IREs behaved quite differently in brains with AD compared to those with “pathological aging,” i.e., amyloid pathology but no cognitive change. A zebrafish model of a PSEN1 fAD-like mutation showed disturbed expression of IRE-bearing transcripts, supporting iron dyshomeostasis as an early event in young AD brains.

    By analyzing IRE-bearing transcripts from hundreds of genes, the authors show that evidence that transcripts with 3' IREs are stabilized by ferrous iron deficiency is not a general rule. Transcripts of the paradigmatic gene TFRC bearing 3’ IREs were, indeed, stabilized by iron deficiency, but this stabilization was also seen in AD brains where iron is observed to accumulate. This, and other analyses, led the authors to suggest that AD brains may, in fact, be in a state of cellular ferrous iron deficiency camouflaged by an accumulation of ferric iron.

    The amyloid precursor protein translated from the 5'UTR specific IRE-bearing transcript can facilitate ferroportin export of iron from neurons (Duce et al., 2010). This suggests a potential for the presence of cell-based Fe deficits in trisomy 21 Down's syndrome individuals exhibiting one-third more APP gene dose.

    However, the authors of this paper present an intriguing model of brain Fe-II deficiency with Fe-III surfeit that would, in fact, be possible if failure of lysosomal acidification led to ferrous iron deficiency, as supported by the work of Yambire et al. (2019). Interestingly, this hypothesis is consistent with the regulation of APP expression by its own 5' IRE, which suppresses APP protein translation when cells are deficient in ferrous iron.

    Jiang, Nixon (2019) and colleagues showed that modest increases in APP expression can cause changes in lysosomal pH since this is modulated by APP's β-CTF fragment. They showed that overexpression of β-CTF due to trisomy 21 in Down's syndrome, or APP gene duplication or fAD mutation, would raise lysosomal pH levels. Such events would inhibit ferrous iron generation.

    In a feedback adaptation, one possibility is that initial low ferrous iron levels should suppress APP translation, β-CTF formation, and keep lysosomal pH sufficiently low to raise cellular ferrous iron levels. This raises the possibility that drugs modulating translation of APP via its IRE might present not only as anti-amyloid agents, they could be used to correct lysosomal acidification deficits toward therapeutic actions to prevent ferroptosis in individuals with Alzheimer's disease or Down syndrome (Rogers and Cahill, 2020).

    References:

    . Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer's disease. Cell. 2010 Sep 17;142(6):857-67. PubMed.

    . Impaired lysosomal acidification triggers iron deficiency and inflammation in vivo. Elife. 2019 Dec 3;8 PubMed.

    . Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-βCTF (C99). J Neurosci. 2019 Jul 3;39(27):5255-5268. Epub 2019 May 1 PubMed.

    . Iron-responsive-like elements and neurodegenerative ferroptosis. Learn Mem. 2020 Sep;27(9):395-413. Print 2020 Sep PubMed.

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