Viral delivery of abnormal tau into subiculum projecting entorhinal cells impairs temporal‐association memory in a mouse model of early Alzheimer's Disease
Bibliographic record
Abstract
BACKGROUND: Among the earliest signs of preclinical Alzheimer's disease (AD) are navigation impairments and the presence of abnormal hyperphosphorylated tau (aTau) proteins in the entorhinal cortex (EC), a brain region that encodes space and movement. As AD progresses and memory impairments develop, EC aTau spreads to the subiculum (Sub), a key region for memory encoding and recall. To better understand the impact of aTau progression from EC to Sub on neurophysiology and memory we designed a mouse model that seeds human mutant tau in Sub projecting EC neurons. METHOD: To best approximate the spread of aTau in early AD, we injected a cre-dependent virus that selectively deposits mutant human tau (AAV2/9-Flex-P301L-GFP) in a transgenic mouse line that limits cre expression to EC layers 2/3 cells (tg(Oxr-1cre)C14Stl/J). By injecting into Sub, only cre+ cells projecting to Sub are initially transfected by the virus. Male and female mice were given between 4 weeks to 12 months for aTau to express. Mice were then tested on spatial memory (water maze), temporal-association & contextual memory (trace-fear conditioning), and anxiety (elevated plus maze) tasks. Task performance was compared to cre -/- littermates who received the same virus injections but did not express the tau virus. RESULTS: Our viral strategy effectively limited transfection to Sub projecting EC layer 2/3 neurons. Immunofluorescence imaging confirmed that both human tau (AT7) and phosphorylated tau (AT8) were present in the EC-Sub circuit as early as 4 weeks post injection. Mice with hyperphosphorylated tau in Sub projecting EC neurons showed impaired trace memory (p = 0.027) while spatial and contextual memory remained intact. There were no differences in anxiety levels. CONCLUSION: We have shown that selective delivery of human mutant tau to the EC-Sub circuit impairs temporal-association memory. These data are in line with previous reports of circuit inactivations disrupting association memory, and offer a new model to probe specific memory loss and guide interventions to slow aTau spread and rescue memory.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".