ArticleAlzheimer's research & therapy2024
Alpha-lipoic acid alleviates cognitive deficits in transgenic APP23/PS45 mice through a mitophagy-mediated increase in ADAM10 α-secretase cleavage of APP.
Article in Alzheimer's research & therapy, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- When copper turns killer: Decoding copper dyshomeostasis and cuproptosis in neurodegenerative pathogenesis and precision metal interventions.Neural regeneration research · 2026Article
- Alpha-Lipoic Acid and Biotin in Neurodegenerative Diseases: Convergent Mechanistic Insights from Preclinical Models to Clinical Perspectives.Neurology international · 2026Review
- Effect of ALA on preventing diabetic peripheral neuropathy in rats through mitochondrial axonal transport.PloS one · 2026Article
- Meningeal lymphatics as a therapeutic target for neurodegenerative disorders.Translational neurodegeneration · 2025Review
- Potential of phytochemicals in the treatment of Alzheimer disease by modulating lysosomal dysfunction: a systematic review.Chinese medicine · 2025Review
- Expression of Reelin, Aβ1-42, Tau and FTH1 in Idiopathic Epiretinal Membranes: Exploring the Link Between Reelin and Neurodegenerative Biomarkers.Biomolecules · 2025Article
- Therapeutic Potential of Alpha-Lipoic Acid: Unraveling Its Role in Oxidative Stress and Inflammatory Conditions.Current issues in molecular biology · 2025Review
- Advances in α-Lipoic Acid for Disease Prevention: Mechanisms and Therapeutic Insights.Molecules (Basel, Switzerland) · 2025Review
- The role and therapeutic potential of mitophagy in major depressive disorder.Frontiers in pharmacology · 2025Review
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9 authors.
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Abstract
backgroundAlpha-lipoic acid (ALA) has a neuroprotective effect on neurodegenerative diseases. In the clinic, ALA can improve cognitive impairments in patients with Alzheimer's disease (AD) and other dementias. Animal studies have confirmed the anti-amyloidosis effect of ALA, but its underlying mechanism remains unclear. In particular, the role of ALA in amyloid-β precursor protein (APP) metabolism has not been fully elucidated.
objectiveTo investigate whether ALA can reduce the amyloidogenic effect of APP in a transgenic mouse model of AD, and to study the mechanism underlying this effect.
methodsALA was infused into 2-month-old APP23/PS45 transgenic mice for 4 consecutive months and their cognitive function and AD-like pathology were then evaluated. An ALA drug concentration gradient was applied to 20E2 cells in vitro to evaluate its effect on the expression of APP proteolytic enzymes and metabolites. The mechanism by which ALA affects APP processing was studied using GI254023X, an inhibitor of A Disintegrin and Metalloproteinase 10 (ADAM10), as well as the mitochondrial toxic drug carbonyl cyanide m-chlorophenylhydrazone (CCCP).
resultsAdministration of ALA ameliorated amyloid plaque neuropathology in the brain tissue of APP23/PS45 mice and reduced learning and memory impairment. ALA also increased the expression of ADAM10 in 20E2 cells and the non-amyloidogenic processing of APP to produce the 83 amino acid C-terminal fragment (C83). In addition to activating autophagy, ALA also significantly promoted mitophagy. BNIP3L-knockdown reduced the mat/pro ratio of ADAM10. By using CCCP, ALA was found to regulate BNIP3L-mediated mitophagy, thereby promoting the α-cleavage of APP.
conclusionsThe enhanced α-secretase cleavage of APP by ADAM10 is the primary mechanism through which ALA ameliorates the cognitive deficits in APP23/PS45 transgenic mice. BNIP3L-mediated mitophagy contributes to the anti-amyloid properties of ALA by facilitating the maturation of ADAM10. This study provides novel experimental evidence for the treatment of AD with ALA.
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