Mitochondria Directed Oxidative Stress and Metal Abnormalities at the Center of Alzheimer’s Disease

For nearly four decades, our research has focused on dissecting the cytopathology of Alzheimer’s disease (AD) with the goal of developing a cure. We have used oxidative stress as a window to view and understand AD. Oxidative damage to sugars, proteins, lipids, and nucleic acids increases in neuronal cytoplasm. The same neuronal compartment has increased redoxactive iron and copper, which can catalyze oxidative damage, and likely derive from mitochondrial debris (in and outside lysosomes) including cytochromes, mitochondria-specific prosthetic groups, and mtDNA. Mitochondria show altered axonal transport, size distribution, energetics, fusion/fission, and degradation in AD that correlate with the extent of oxidative damage suggesting they are the origin. Synaptic mitochondria abnormalities correlate with synaptic vesicular changes. Surprisingly, amyloidβ and tau are quantitatively associated with reduced neuronal oxidative damage. Copper sequestration by amyloidβ blocks copper-mediated oxidation of lipids and vitamin C indicating amyloidβ can be a protective response rather than the initiator of AD. Instead of being bound to amyloidβ, iron is present as 10nm magnetite crystals with super-paramagnetic properties as well as abundant metallic iron, along with metallic copper. This is the first report of metallic iron and copper in humans. Not just amyloidβ, but also tau, may be protective responses induced in AD to maintain neurons with altered balance for decades. While these studies put oxidative stress at the center of AD, they also highlight a complexity of multifaceted alterations that is homeostatic and requires a deeper level of understanding before an effective cure.