Targeting Ferroptosis In Alzheimer's Disease: From Biochemistry To Clinical Trial
Speaker: Professor Scott Ayton
Director of the Centre of Research Excellence in Enhanced Dementia Diagnosis (CREEDD)
The Florey Institute
Melbourne
Title: Targeting Ferroptosis In Alzheimer's Disease: From Biochemistry To Clinical Trial
Abstract: Alzheimer's disease (AD) is defined by β-amyloid plaques and tau-containing neurofibrillary tangles, but the ensuing cellular derangements that culminate in neurodegeneration remain elusive. Iron elevation is a co-pathology in Alzheimer's disease that has the potential to cause neurodegeneration by ferroptosis, an iron dependent cell death pathway that is prevented by the checkpoint protein GPX4, which consumes glutathione (GSH). We conducted a clinical trial of the iron chelator, deferiprone, and we found that it markedly accelerated disease progression, which provided new insights into iron neurobiology, but also precludes its utility as a drug target for ferroptosis in AD. To interrogate new targets, we performed proteomics on the inferior temporal cortex of 625 subjects along a continuum of clinical and pathological changes in AD, which revealed a prominent depletion of mitochondrial proteins. Biogenetic insufficiency in AD was reflected by a concurrent loss of GSH, which requires 2 ATP for its synthesis, and genetic and pharmacologic ATP depletion models confirmed that ATP is rate-limiting for GSH. Accordingly, an unbiased association analysis uncovered mitochondrial proteins in positive correlation with total GSH (GSH) in AD subjects. Mitochondria therefore control GSH flux, and loss of energy output is consequently demonstrated as a liability for ferroptosis in AD.
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Neuroscience seminars at the QBI play a major role in the advancement of neuroscience in the Asia-Pacific region. The primary goal of these seminars is to promote excellence in neuroscience through the exchange of ideas, establishing new collaborations and augmenting partnerships already in place.
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