Distinct patterns of oligodendroglial dysfunction in neurodegenerative diseases
Bibliographic record
Abstract
BACKGROUND: Oligodendroglia are a major class of glial cell that play critical roles in myelination and neuronal support. Involvement of oligodendroglia is well-known pathologically in frontotemporal lobar degeneration with tau (FTLD-tau) and TDP-43 (FTLD-TDP) pathology, Alzheimer's disease (AD) and multiple system atrophy (MSA). However, their contribution to the pathogenesis of neurodegenerative disorders is underappreciated. This study investigated the impact of misfolded proteins including tau, TDP-43, and a-synuclein on the cellular characteristics of oligodendroglia and myelination. METHOD: 82 cases were selected including controls (n = 5), AD (n = 10), FTLD-tau (n = 38), FTLD-TDP (n = 9), motor neuron disease (n = 10) and MSA (n = 10). Sections from two brain regions were examined: a pathological predilection site and minimally affected region, and immunostained for markers of oligodendroglia (tubulin polymerisation promoting protein, TPPP) and myelin (CNPase, PLP, MAG, MOG), and AT8, pTDP-43 or a-synuclein. Three cases of each group were selected for double-labelled immunofluorescence to determine co-localisation patterns. Density of oligodendroglial inclusions were assessed and oligodendroglial dysfunction measured by nuclear enlargement and fragmentation, assessment of TPPP-immunostaining, co-expression of TPPP with mis-folded proteins, and assessment of myelin integrity. RESULT: Oligodendroglial inclusions were identified in all cases with the highest density found in MSA, FTLD-tau subtypes and AD, followed by FTLD-TDP and MND. Few oligodendroglial inclusions were found in the minimally affected region. In all groups, oligodendroglia with tau, TDP-43 and a-synuclein inclusions showed nuclear enlargement (p <0.001) and fragmentation (p <0.001) compared to controls and oligodendroglia without inclusions. Size of oligodendroglial nuclei with inclusions differed between groups and were most pronounced in MSA and cases with tau inclusions. TPPP mislocalised from the nucleus and cytoplasmic immunoreactivity differed between groups. Cytoplasmic TPPP-immunoreactivity co-localised with pathological protein inclusions. Myelin integrity was intact in all brain regions of control cases. Disruption of myelin integrity was prominent in all groups and was most pronounced in the pathological predilection area. Of all cases, those with AD, MSA and Pick's disease had the most severe disruption to myelin integrity. CONCLUSION: This study highlights the distinct cell-intrinsic impact of mis-folded protein pathology on oligodendroglia and identifies unique signatures of oligodendroglial dysfunction that are likely to adversely affect neuronal and axonal function.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".