Hampered AMPK-ULK1 cascade in Alzheimer’s disease (AD) instigates mitochondria dysfunctions and AD-related alterations that are alleviated by metformin
Bibliographic record
Abstract
Abstract Background Mitochondrial structure and function alterations are key pathological features in Alzheimer’s disease (AD) brains. The adenosine monophosphate-activated protein kinase (AMPK) and its downstream effector Unc-51 like autophagy activating kinase 1 (ULK1) represent a key node controlling mitochondria health, the alteration of which likely contribute to AD development. Methods We designed this study to investigate AMPK-ULK1 activation state in post-mortem human sporadic AD brains, in 3xTgAD mice that recapitulate most of human AD features, and in neuronal cells expressing the amyloid precursor protein with the familial Swedish mutation (APPswe). We examined the impact of the pharmacological and genetic modulation of AMPK-ULK1 cascade on mitochondria structure and functions in APPswe cells. We evaluated the potential beneficial impact of AMPK-ULK1 activation by Metformin (Met) on mitochondria defects, as well as on early- and late-stage AD-related alterations in vivo and ex vivo . Results At first, we show that AMPK-ULK1 cascade is defective in murine and human AD brains as well as in APPswe cells. We then report that Met administration to 3xTgAD mice alleviates the alterations of neuronal mitochondria structure and function and we consolidate these results in cells using both pharmacological and genetic tools to modulate AMPK-ULK1 cascade. In mice brains, Met reduces the early accumulation of APP C-terminal fragments (APP-CTFs) as well as the amyloid beta (Aβ) burden present in aged mice. Mechanistically, we show that Met increases the localization of APP-CTFs within cathepsin D-positive lysosomal compartments in vivo and enhances cathepsin D activity in vitro . The reduction of Aβ load by Met occurs through an increased recruitment of Iba1 + cells to Aβ plaques and an enhancement of the phagocytic activity of microglia. Accordingly, in symptomatic 3xTgAD mice, Met alleviates microgliosis and astrogliosis, modulates microglia morphology, reduces peripheral proinflammatory cytokines levels, and regulates the expression of a set of inflammatory genes. In addition, Met normalizes dendritic spines shape in organotypic hippocampal slice cultures modeling AD and improves learning performance of 3xTgAD mice. Conclusions Our study demonstrates potential therapeutic benefits of targeting AMPK-ULK1 cascade to reverse both early and late AD-related alterations, deserving further investigation in fundamental research and in human clinical studies.
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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 | 0.001 |
| 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".