Familial Alzheimer’s disease (fAD) mutations in the amyloid-β protein precursor (AβPP) enhance brain AβPP C-Terminal Fragment (CTF) levels to inhibit lysosomal v-ATPase. Consequent disrupted acidification of the endolysosomal pathway may trigger brain iron deficiencies and mitochondrial dysfunction. The iron responsive element (IRE) in the 5’Untranslated-region of AβPP mRNA should be factored into this cycle where reduced bioavailable Fe-II would decrease IRE-dependent AβPP translation and levels of APP-CTFβ in a cycle to adaptively restore iron homeostasis while increases of transferrin-receptors is evident. In healthy younger individuals, Fe-dependent translational modulation of AβPP is part of the neuroprotective function of sAβPPα with its role in iron transport.
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