Giant spider neurons uncover a myelin-derived waste-internalizing canal system that fails in neurodegeneration

The underlying causes for Alzheimer disease are presumed to lie in failed waste removal from the brain. However, the mechanisms by which waste is cleared from neurons, and how this system fails in neurodegeneration are poorly understood. A novel 'glial-canal-hypothesis' postulates that myelin-forming macroglia give rise to waste internalizing canals that project into neuronal somata and remove cellular debris in an aquaporin4-dependent manner. We postulate that abnormal swelling of the aquaporin4-expressing glial cells leads to spongiform abnormalities, gradual depletion, and death of associated neurons. Due to the novelty of this postulation little is known about the cellular architecture of this canal system that was first discovered in giant neurons of the wandering spider <i>Cupiennius salei</i> . Here we have utilized histological, ultrastructural and immunohistochemical methods to describe the structural foundation of this glial canal system in giant spider neurons in which waste-internalizing canals and associated structures are clearly visible. Sequencing the spider genome, we show compelling homologies of key proteins that are implicated in neurodegeneration between phylogenetically distant species. Based on this work, we provide a testable functional hypothesis regarding waste removal from neuronal somata and how this system fails in neurodegeneration. We highlight structural similarities of this system in rodent and human brain. Supported by the findings presented here we postulate that ( <i>i</i> ) neurodegeneration in <i>C. salei</i> may be caused by hypertrophic swelling of myelin-forming waste-internalizing macroglia, and ( <i>ii</i> ) that a similar canal system, although structurally modified, is likely highly conserved in the mammalian brain.