Fig. 4.

Correlation between iron overload and three dementia-associated diseases: A AD: iron overload causes Aβ aggregation by acting on the IRE site of APP mRNA and interaction with Aβ. Iron promotes the phosphorylation of tau by activating the CDK5/P25 complex and GSK-3β to form neurofibrillary tangles. The positive feedback loop among iron accumulation, oxidative stress, Aβ aggregation, and tau hyperphosphorylation causes neuron death. B PD: Within the synapse, dopamine can be broken down to DOPAL and inactivated by two enzymes including MAO and COMT. H2O2 is a normal product of monoamine oxidation via MAO. H2O2 can participate in the Fenton reaction and produce highly active free radicals. DOPAL can modify ɑ-Synuclein and lead to its aggregation. In addition, iron directly induces ɑ-Synuclein expression and aggregation. C Stroke: low oxygen condition caused by ischemic stroke leads to more iron influx into the brain. Acidic pH leads to dissociation of Fe³⁺ from transferrin and its reduction to Fe²⁺ thereby NTBI uptake occurs by neurons. Harmful oxidation products caused by Fenton/Haber–Weiss reaction induce neuron death. AD, Alzheimer’s disease; PD, Parkinson’s disease; CDK5, cyclin-dependent kinase; GSK-3β, glycogen synthase kinase-3β; MAO, monoamine oxidase; COMT, catechol-O-methyl transferase; IRE, iron-responsive element; APP, amyloid precursor protein; DOPAL, 3,4-dihydroxyphenylacetaldehyde. This Figure was created by powerPoint and Adobe Illustrator