Reduced cholinergic tone and hippocampal‐dependent cognitive impairments in APP <sup>NL‐F</sup> mice
Bibliographic record
Abstract
Abstract Background The prevailing model of Alzheimer's disease (AD) proposes that the accumulation of misfolded amyloid‐beta (Aβ) peptides drives tau protein hyperphosphorylation and neuroinflammation, leading to neurodegeneration and cognitive decline. However, current therapeutic approaches targeting Aβ show only subtle effects on cognitive deficits. Interestingly, the loss of cholinergic neurons of the basal forebrain precedes and predicts pathology and neurodegeneration in AD. The vesicular acetylcholine transporter (VAChT), a key regulator of cholinergic signalling, functions at the presynaptic terminal by loading acetylcholine (ACh) into vesicles for secretion. Notably, VAChT expression is significantly reduced in AD brains, with changes observed early in disease progression. Whether these early changes in cholinergic synaptic function contribute to hippocampal dysfunction remains unclear. Using the APP NL‐F mouse model of AD, which expresses humanized Aβ with familial AD mutations, this study investigates the interplay between cholinergic signalling and hippocampal‐dependent cognitive function. Method ACh signalling was recorded using fibre photometry and the GRAB ACh sensor in the hippocampal CA1 region of freely behaving APP NL‐F and control mice performing the Trial‐Unique delayed Nonmatching‐to‐Location (TUNL) task. This task assesses spatial working memory, a cognitive domain impaired in AD. Large and small separation windows were used to challenge spatial discrimination. Result Analysis of VAChT levels have shown some dynamic regulation, but with aging VAChT levels decreased substantially. Recordings of ACh dynamics in the hippocampal CA1 region revealed behaviour‐associated changes, particularly during screen approaches, touches, and predominantly reward responses. Cholinergic tone decreases substantially in response to reward, demonstrating tonic ACh signalling that can change in response to specific stimuli. Young APP NL‐F mice, tested before substantial plaque accumulation, exhibit deficits in spatial working memory during challenging conditions, which associated with reduced cholinergic responses. The deficit in cholinergic tone in APP NL‐F mice closely mirrors the cholinergic dysfunction observed in the forebrain VAChT knock‐out mice, which showed pronounced impairments in learning, memory, and ACh signalling during the TUNL task. Conclusion These findings highlight the role of early deficits in cholinergic synaptic function associated with spatial memory impairments before overt pathology in APP NL‐F mice. Future experiments aim to develop strategies to rescue memory and cholinergic tone dysfunction.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.003 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 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".