Abstract
One of the most important goals in biomedical sciences is understanding the causal mechanisms of neurodegeneration. A prevalent hypothesis relates to impaired waste clearance mechanisms from the brain due to reported waste aggregation in the brains of Alzheimer patients, including amyloid-β plaques and neurofibrillary tau tangles. Currently, our understanding of the mechanisms by which waste is removed from the brain is only fragmentary. Here we provide compelling evidence that waste clearance from brain tissue is highly conserved in arachnids and humans. Utilizing RNAscope in situ hybridization, immunohistochemical, ultrastructural, and histological approaches, we demonstrate that cellular debris in spider neurons is engulfed by myelin-forming ependymal glial cells that transect into neuronal somata and form myelin-derived waste-internalizing receptacles. These canal systems channel this debris into the lymphatic system likely in an aquaporin-4 (AQP4) water channel-dependent manner. We provide robust evidence that a similar process may be true in human hippocampus where vast numbers of myelinated AQP4-immunoreactive ependymal glial cells send cellular projections into the somata of neurons and glial cells where they differentiate into waste internalizing receptacles. In the brains of Alzheimer decedents, hypertrophic impairment of these myelinated glial cells leads to the catastrophic obstruction and depletion of neuronal cytoplasm into the ependymal glial cells. At the cellular level, the structural impairment of macroglia leads to swelling myelin protrusions that appear as electron-lucent circular profiles, explaining spongiform abnormalities associated with the neurodegenerative diseases described here. We propose to term this novel type of macroglia-mediated cell death "gliaptosis."