Iron Responsiveness to Lysosomal Disruption: A Novel Pathway to Alzheimer's Disease

Familial Alzheimer's disease (fAD) mutations in the amyloid-beta protein precursor (A beta PP) enhance brain A beta PP 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 A beta PP mRNA should be factored into this cycle where reduced bioavailable Fe-II would decrease IRE-dependent A beta PP translation and levels of APP-CTF beta in a cycle to adaptively restore iron homeostasis while increases of transferrin-receptors is evident. In healthy younger individuals, Fe-dependent translational modulation of A beta PP is part of the neuroprotective function of sA beta PP beta with its role in iron transport.