Brain iron dyshomeostasis with iron accumulation is a known feature of brain aging. The cause of this iron accumulation is aging is unknown, but the immune system is less active in older people, and as viruses replicate more efficiently in iron-rich senescent cells, they may have developed the ability to induce this phenotype in aging host tissues.
It has been proposed several times that metal dyshomeostasis could be an underlying mechanism responsible for the initiation and progression of the pathological changes associated with neurodegenerative disorders, including the motor and extra-motor symptoms of ALS.
A new paper proposes an update of the iron hypothesis of Alzheimer's disease (Alzheimer's disease), based on large scale emerging evidence.
Iron featured historically early in Alzheimer's disease research efforts for its involvement in the amyloid and tau proteinopathies, yet iron neurochemistry remains peripheral in mainstream Alzheimer's disease research.
Much of the effort investigating iron in Alzheimer's disease has focused on the potential for iron to provoke the onset of disease, by promoting proteinopathy through increased protein expression, phosphorylation, and aggregation.
The authors provide new evidence from a large post mortem cohort that brain iron levels within the normal range are associated with accelerated ante mortem disease progression in cases with underlying proteinopathic neuropathology.
These results corroborate recent findings that argue for an additional downstream role for iron as an effector of neurodegeneration, acting independently of tau or amyloid pathologies.
The researchers hypothesize that the level of tissue iron is a trait that dictates the probability of neurodegeneration in Alzheimer's disease by ferroptosis.
Ferroptosis is a type of programmed cell death dependent on iron and characterized by the accumulation of lipid peroxides, and is genetically and biochemically distinct from other forms of regulated cell death such as apoptosis.
Ferroptosis is initiated by the failure of the glutathione-dependent antioxidant defenses, resulting in unchecked lipid peroxidation and eventual cell death. Lipophilic antioxidants and iron chelators can prevent ferroptotic cell death.
A substantial body of preclinical evidence and early clinical data has demonstrated that deferoxamine and other iron chelators have strong disease-modifying impacts in Alzheimer's disease, Parkinson's disease, ischemic stroke. Acting by the disease-nonspecific pathway of iron chelation, deferoxamine targets each of these complex diseases via multifactorial mechanisms.
Deferiprone another iron chelator is tested in clinical trials against ALS in France’s Lille CHU hospital.
