Cellular Senescence and Iron Dyshomeostasis in Alzheimer’s Disease
Masaldan S, Belaidi AA, Ayton S, Bush AI. Cellular Senescence and Iron Dyshomeostasis in Alzheimer’s Disease. Pharmaceuticals (Basel). 2019 Jun 19;12(2):93. doi: 10.3390/ph12020093. PMID: 31248150; PMCID: PMC6630536.
The accumulation of Aβ has been the primary target of therapies, but attempt to lower the plaque burden have not been successful in lowering cognitive decline. The homeostatic regulation of iron could be a targetable pathway since there is evidence it is disturbed in neurodegeneration.
Iron is involved in cellular respiration, DNA synthesis, cell division, oxygen transport and neurotransmission. Iron can cycle through oxidation states, which while biologically important, can lead to oxidative damage. There are homeostatic mechanisms designed to regulate iron, but there is also an age-related accumulation of iron in the brain. Iron dyshomeostasis may not get high enough to result in iron toxicity, but its dyshomeostasis could result in increased susceptibility to oxidative dysfunction.
Iron dyshomeostasis and AD
Iron accumulation has been observed in brain regions affected by AD. The intensity of accumulation depends on the subtype of AD and can be used to distinguish between sporadic and familial AD. The forms of iron in AD patients vary in the torque they experience in a magnetic field compared to controls.
Iron is associated with the pathological lesions in AD and it could be that it promotes the aggregation and oligomerization of Aβ peptides. Iron and the iron storage protein ferritin levels are associated with amyloid deposition amount.
Iron could enhance the translation and amyloidogenic processing of amyloid precursor protein by its aberrant binding to APP mRNA. Iron is also involved in tau phosphorylation and aggregation - events mitigated by iron chelation. NFT tau accumulation is associated with the induction of heme oxygenase-1 which releases iron from heme exacerbating oxidative stress.
Iron is associated with the rate of cognitive decline 12 years before death. CSF ferritin levels can predict cognitive decline and the transition from MCI to AD.
Cellular senescence, iron dyshomeostasis and AD
There is increasing evidence that senescence induction in the brain is linked to neurodegeneration and that the removal of senescent cells in the brain leads to improved cognition in mice models.
Senescent cells in vitro show iron dyshomeostasis and their abundance could influence iron levels in ageing tissue. Iron promotes senescence in cultured microglia. Chelators can reduce and prevent the accumulation of iron and ferritin seen in senescence in vitro. Chelating iron in C. elegans led to reduction in iron-dependent oxidation and cell death. The SASP may be a ferritin expression driver in neurons and glia which makes them more susceptible to ferroptosis - iron mediated cell death.
Iron as a therapeutic target
Iron chelators have shown promise in PD and motor neuron disease. A study on iron chelation found that using the chelator deferoxamine over two years slowed the clinical progression of dementia associated with AD. Another study inhibiting zinc and copper ions from binding to Aβ showed a positive effect and reduction in cognitive decline rate for severely affected patients. There was also a decline in Aβ42 in plasma.