Nose to Brain Translocation of Inhaled Ultrafine Elongated Particles: Facts and Mysteries

Uschi M Graham^1*Jayant M Pinto²Jennifer Weuve³Alan K Dozier¹Rick Rogers¹Sukriti Nag, MD, PhD, FRCPC⁴Julie A Schneider⁴Joel D Kaufman⁵David Alan Bennett⁴Gunter Oberdorster⁶

• ¹BioInnovations Institute, Natick, United States
• ²The University of Chicago Medicine, Chicago, United States
• ³Boston University, Boston, United States
• ⁴Rush University Medical Center, Chicago, United States
• ⁵University of Washington, Seattle, United States
• ⁶University of Rochester, Rochester, United States

We are reporting here that inhaled nanosized elongated mineral particles (EMPs) are reaching the human central nervous system (CNS) via two neuronal pathways, cranial nerve I (olfactorius) and cranial nerve V (trigeminus) from deposits on the nasal mucosa. High resolution analytical imaging of autopsied brain tissues from eleven members of a Religious Orders Study (ROS) cohort (Rush Alzheimer’s Disease Center) indicated that EMPs translocate from their nasal deposits to the brain either by the olfactory pathway (presence in olfactory bulb , olfactory tract and amygdala) or by the trigeminal pathway (presence in cerebellum). Sub-nanometer imaging and immunohistochemical (IHC) labeling were used to detect Corpora Amylacea (CA), abundant numbers of endogenous ferritin nanoparticles, and myelin damage as indicators of inflammation or oxidative stress. The majority of EMP in the olfactory bulb (OB) were identified as inorganic crystalline and amorphous SiO2 fibers. Amphibole-like fibers (Mg/Si/Fe) were present as well as (length from 25 up to 200 nm), as well as lengthened nano plastics and metallic or carbonaceous fibers. Extensive and consistent demyelination, phosphorylation, wall thickening and CA bodies (size ranging from 10 nm to ~10 m) are present in all studied brain tissues. EMPs are frequently seen inside and outside of CA bodies that occur in close proximity to neurons with myelin damage. The majority of EMPs show shedding of nanosized fiber fragments and ions from their long fiber surfaces and the formation of carbon-rich coronas (physiochemical alterations: bioprocessing). Similar to spherical nanoparticles, EMPs show a tendency to bioprocess which involves interacting with microglia, astrocytes and CA. Concluding, we like to add that though the finding of ambient EMPs in OB, amygdala and cerebellum of human brains, is consistent with neuronal translocation from nasal deposits of inhaled EMPs to the human CNS, we consider it an important goal for future studies to investigate contribution of nano-EMPs from the blood compartment by crossing the BBB and other potential entry routes to the CNS.