Biometals such as copper (Cu) and zinc (Zn) play critical roles in the normal functioning of the brain. Dysregulation of these metals is inherently linked to neurodegenerative disorders. In conditions like Alzheimer's disease (AD), the bonding environment in the brain changes, for instance, due to the accumulation and aggregation of amyloid-beta (Aβ) plaques. These alterations can lead to measurable shifts in the relative abundances of the natural stable isotopes of Cu and Zn in the affected regions through a process known as isotope fractionation.
These isotopic changes in brain tissues can be transferred to other bodily reservoirs, such as blood fractions, through various biological processes. During the ERC Pristine project, the Principal Investigator (PI) developed highly sensitive and precise methods to analyze the stable isotopic compositions of these metals, including Cu and Zn. These methods have enabled confirmation of the hypothesis in multiple murine models of AD. In particular, we have also validated this hypothesis in a small set of post-mortem human brain tissues, showcasing the application of geochemical and cosmochemical methodologies to medical science.
Building on this foundation, this project aims to validate the following hypotheses:
Excursions in Cu and Zn isotope compositions observed in brain tissues during AD progression (previously confirmed in post-mortem human samples) are also reflected in changes in the isotopic compositions of body fluid fractions.
Based on recent findings that Cu and Zn isotope compositions in human brain tissues correlate with Braak stages (a metric for AD progression based on neurofibrillary tangles), it is further hypothesized that the magnitude of isotopic excursions will correspond to Braak stage severity in bodily fluids, mirroring the pattern observed in brain tissues.
