Biology subjects

Fabian-Fine, R.

Publications and source records attributed to Fabian-Fine, R..

3 recordsLinked to original sources

bioRxiv2026

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 Cupiennius salei. 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) neurodegeneration in C. salei may be caused by hypertrophic swelling of myelin-forming waste-internalizing macroglia, and (ii) that a similar canal system, although structurally modified, is likely highly conserved in the mammalian brain.

neuroscience↗

bioRxiv2025

Uncovering the invisible giant: Amyloid β plaques and their proposed association with waste removal in Alzheimer-affected human hippocampus

According to the prevalent Amyloid Hypothesis, the underlying cause for neurodegeneration in Alzheimer Disease (AD) is attributed to the accumulation of misfolded Amyloid {beta} and tau protein in the form of extracellular sticky plaques and neurofibrillary tangles respectively. These protein accumulations are thought to be caused by impaired waste removal. In an alternative hypothesis, we have proposed the existence of an extensive glial canal system that is likely formed by myelinated aquaporin-4 (AQP4)-expressing tanycytes and removes cellular waste from the hippocampal formation. Here, we demonstrate that tanycyte-derived waste-internalizing receptacles are immunoreactive for A{beta} and emanate from specialized nucleus-like organelles in the following referred to as tanysomes. Utilizing RNA-scope in situ hybridization, we demonstrate that these receptacle-forming tanysomes express RNA for AQP4 and the A{beta}-related genes, amyloid precursor protein, and presenilin 1. These findings suggest that A{beta} is likely synthesized where receptacle formation is observed and that A{beta} may play an important structural role in receptacle formation. In AD-affected hippocampus excessive amounts of A{beta}-immunoreactive waste receptacles emerge from tanysomes and have the appearance of plaques in A{beta}-immunolabeled hippocampus. Moreover, we demonstrate that the same receptacle-forming organelles exhibit strong immunolabeling for hyperphosphorylated tau protein in AD-affected tissue. We postulate that both proteins may play important structural roles in waste uptake and that hypertrophic swelling of impaired tanycytes in AD-affected brain may be due to obstructions of this extensive interconnected glial canal system.

neuroscience↗

bioRxiv2025

Alzheimer Disease: The proposed role of tanycytes in the formation of tau tangles and amyloid beta plaques in human brain

The causes of Alzheimer Disease (AD) are attributed to the formation of abnormal protein deposits including tau tangles and Amyloid {beta} (A{beta}) plaques. These proteins are believed to accumulate in the cortex due to impaired waste removal resulting in neurodegeneration. Interestingly, removal of these protein accumulations has failed to halt disease progression. How can this be explained? We have recently proposed the existence of a tanycyte-derived canal-system in the brain that likely internalizes neuronal waste. We propose that A{beta} and tau protein may play important structural roles in this canal system that swells in AD-affected brain. Using in situ hybridization, immunohistochemistry, ultrastructural, and histological methodologies, here we demonstrate the formation of receptacles from translucent swell-bodies that form along tanycyte processes. We show that both spatial distribution and anatomical appearance of swell-bodies differ from myelin-forming ependymal tanycytes. Interestingly, receptacles that differentiate within swell-bodies express mRNA for aquaporin4 and the AD-related proteins Presenilin1 and amyloid precursor protein. Consistent with these findings we show strong A{beta} immunolabeling of these receptacles that swell and proliferate in AD-affected brain and take on the appearance of A{beta} plaques. We conclude that it is likely pathological abnormalities of the associated tanycytes leads to this abnormal swelling.

neuroscience↗