Intraneuronal binding of amyloid beta with reelin - implications for the onset of Alzheimer’s disease
Bibliographic record
Abstract
Abstract It was recently shown that in anteriolateral entorhinal cortex layer II neurons (ECLII neurons) in McGill-R-Thy1-APP homozygous transgenic rats (a model commonly used to study Alzheimer’s disease (AD)), the glycoprotein reelin and intracellular amyloid- β (A β ) engage in a direct protein–protein interaction. Numerous studies of the human brain supported by experimental results from rodent and cell models point to a role for intracellular oligomeric A β in the onset of AD. If reelin functions as a sink for intracellular A β and if the binding to reelin makes A β physiologically inert, it implies that reelin may prevent the neuron from being exposed to the detrimental effects typically associated with oligomeric A β . Considering that reelin expression is extraordinarily high in the major subset of ECLII neurons compared to most other cortical neurons, such a protective role appears very difficult to reconcile with the fact that ECLII is clearly a major cradle for the onset of AD in humans. Here we show that this conundrum may be resolved if ECLII neurons have a much higher maximum production capacity of A β than neurons expressing low levels of reelin. We provide a rationale for why this difference has evolved, and argue that the higher maximum production capacity of A β in ECLII neurons may in a senescent A β -inducing physiology predispose these neurons to initiate AD development. Author summary Amyloid- β is a small peptide that is widely recognized as one of the main culprits involved in the development of Alzheimer’s disease. It was recently shown that in the major subset of neurons in entorhinal cortex layer II, which expresses high levels of the protein reelin, amyloid- β and reelin bind to each other. These neurons, which are strongly involved in memory formation, are among the first to die in subjects with Alzheimer’s disease. If intracellular amyloid- β , which is clearly involved in the onset of the disease, becomes physiologically inert when it binds to reelin, it implies that reelin can prevent the neuron from being exposed to the detrimental effects of increased levels of amyloid- β . Considering that reelin expression is extraordinarily high in ECLII neurons compared to most other cortical neurons, such a protective role appears very difficult to reconcile with the fact that ECLII constitute the predominant cortical site for initiation of Alzheimer’s disease. Here, we show that this paradox may be resolved if ECLII neurons have a much higher maximum amyloid- β production capacity than neurons expressing low levels of reelin. We provide reasons why this difference has evolved and argue that it, in a senescent physiology, predisposes ECLII neurons to initiate the development of Alzheimer’s disease.
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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 | 0.000 | 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".