CURRENT ACCREDITATIONS
Zebrafish K592 / M593 model
Zebrafish equivalent of Swedish mutation (APP K670N/M671L)
Model Background
The Swedish mutation (APP K670N/M671L) is a well-established, pathogenic double mutation associated with familial Alzheimer's disease (AD). Located immediately adjacent to the β-secretase cleavage site of amyloid precursor protein (APP), this mutation enhances BACE1-mediated APP processing, resulting in increased amyloid-beta (Aβ) production and contributing to the development of amyloid pathology. Its well-characterized molecular mechanism has made it a cornerstone of preclinical Alzheimer's disease research, with widespread incorporation into established transgenic mouse models, including Tg2576, APP23, and 5xFAD.
In zebrafish (Danio rerio), the K592 and M593 residues of the appb gene have been identified as the corresponding positions within the conserved APP β-secretase cleavage region. Introducing the K592N/M593L double mutation at these positions offers a genetically targeted approach to recapitulating the human Swedish mutation in a zebrafish model.
This genetic correspondence provides a strong scientific rationale for developing a zebrafish-based model of familial Alzheimer's disease. By targeting the conserved molecular region implicated in amyloidogenic APP processing, the model has the potential to reproduce key aspects of Swedish mutation-associated pathology, providing a complementary in vivo platform for investigating Aβ production, aggregation, and therapeutic interventions.
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Amyloid-Beta Aggregation and Clearance Assays
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Quantitative Aβ aggregation burden.
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Soluble and insoluble Aβ fractions.
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Aβ42 and Aβ40 concentrations.
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Aβ42/Aβ40 ratio.
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Aβ oligomer and protofibril levels.
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Concentration-dependent reduction in aggregation.
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Time-dependent changes in amyloid pathology.
Therapeutic Efficacy and Candidate Screening
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Dose-response relationships.
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Minimum effective concentration.
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Therapeutic efficacy over time.
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Brain exposure and distribution.
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Behavioral phenotypes associated with neurological dysfunction.
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Early safety and toxicity assessment.
Model Validation Data - 8 Day Screening programme
Characterization of Aβ levels in response to Lanabecestat
Dosing for three days, screening on day 8 dpf.
Soluble amyloid-beta (Aβ) comprises non-deposited Aβ species, including monomers and soluble oligomeric aggregates, which are implicated in synaptic dysfunction and neurotoxicity associated with Alzheimer's disease.
Insoluble amyloid-beta (Aβ) comprises aggregated Aβ species, predominantly fibrillar structures associated with amyloid plaque formation, representing a key pathological hallmark of Alzheimer's disease.
Quantification of Aβ oligomers serves as a key preclinical endpoint for assessing early amyloid pathology, neurotoxicity, and the therapeutic efficacy of anti-amyloid interventions.
Quantification of Aβ protofibrils serves as a critical preclinical endpoint for assessing amyloid aggregation, disease-associated neurotoxicity, and the therapeutic efficacy of protofibril-targeting interventions.
The amyloid-beta 42 to 40 (Aβ42/Aβ40) ratio is an important biomarker reflecting the relative production of aggregation-prone Aβ42 compared with Aβ40, providing insights into amyloid precursor protein (APP) processing and Alzheimer's disease-associated amyloid pathology.