Professor of Neuroscience and Psychiatry
Florey Institute of Neuroscience and Mental Health, The University of Melbourne
Host: Brent Stockwell
Title: Iron and ferroptosis in the pathogenesis of Alzheimer’s Disease
Abstract: Alzheimer's disease (AD) is an incurable and increasingly prevalent dementia, with major risk factors being age and the APOE-e4 allele. AD has a hallmark neuropathology of neuronal death, oxidative damage, extracellular Ab amyloid and intracellular tau deposition in the brain. There is also marked dysregulation of metal homeostasis, with iron elevation reported in cortex (AD) in tandem with the proteinopathies. The major proteins implicated in AD have been found to function in an iron regulatory system that fails in aging, and aging itself is complicated by an inevitable increase in brain iron. The amyloid protein precursor (APP), like ceruloplasmin (CP), facilitates the export of iron from cells by stabilizing cell surface ferroportin, and prevents dietary iron from accumulating in the brain. Tau impacts on iron export by trafficking APP to the cell surface. CSF ferritin levels predict cognitive decline and conversion of MCI to AD, and are associated with Apolipoprotein E levels. In vivo measurement of brain iron by QSM strongly adds to the prediction of cognitive decline in tandem with amyloid PET scans. These evidences, as well as a host of specific post-mortem changes, converge on the novel cell death program, ferroptosis, as the pathogenic mechanism of AD. Small molecules that suppress ferroptosis have been effective in animal models of neurodegenerative disease, and a recent phase 2 clinical trial of the anti-ferroptotic chelator deferiprone in Parkinson’s disease lowered nigral iron and improved clinical readouts. On this basis, we are currently testing of deferiprone in a phase 2 randomized controlled trial for AD.
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Belaidi, A. A. & Bush, A. I. Iron neurochemistry in Alzheimer‘s disease and Parkinson’s disease: targets for therapeutics. J Neurochem 139 Suppl 1, 179–197 (2016).
Ayton, S., Faux, N. G. & Bush, A. I. Association of Cerebrospinal Fluid Ferritin Level With Preclinical Cognitive Decline in APOE-ε4 Carriers. JAMA Neurol 74, 122–125 (2017).
Ayton, S, et al. Cerebral quantitative susceptibility mapping predicts β-amyloid-related cognitive decline. Brain, 140, 2112–2119 (2017).
Ayton, S., Diouf, I. & Bush, A. I. Evidence that iron accelerates Alzheimer’s pathology: a CSF biomarker study. Journal of Neurology, Neurosurgery & Psychiatry doi:10.1136/jnnp-2017-316551 (2017)..
Stockwell, B. R., Angeli, J. P. F., Bayir, H., Bush, A. I., Conrad, M., Dixon, S. J., et al. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell, 171, 273–285. (2017).