Nano-imaging of Alzheimer’s neuritic plaques to reveal at organelle level the role of tau protein in metal dyshomeostasis

Alzheimer’s disease is characterized by deposition of amyloid β (Aβ) plaques and intraneuronal neurofibrillary tangles (NFT) in brain tissues. Accumulation of NFT made of hyperphosphorylated fibrillar forms of the tau (τ) protein correlates with decline of the cognitive function. These changes are likely related to dramatic perturbations in the homeostasis of Fe and other metals. Our aim is to assess at <50 nm resolution the changes in elemental composition in the brain tissue at the level of amyloid plaques as a function of τ accumulation. Based on our published methodology to image and quantify metals at the subcellular level in brain tissues, the goals of this proposal are: nanoimaging by phase contrast and XRF, of regions around Aβ plaques in the cortex of 5xFAD mice. In the cellular sub-compartments identified by TEM and phase contrast we will quantify metals to assess the effects of human τ overexpression on their levels and distribution. We request 15 shifts.