Alzheimer’s Disease Models

Alzheimer's disease-relevant strains that are sequence validated

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Alzheimer's disease is one of the most economically and socially impactful diseases of our time. Through basic and clinical research, top genes that are mutated in Alzheimer's disease have been identified.

However, it is complex and challenging to select the right mutants to study due to too many choices of strains and alleles (genetic models). In addition, researchers sometimes have doubts that a strain obtained from another source has not lost the mutation or undergone genetic drift.

Our goal is to create a curated, reliable library of strains that are relevant to Alzheimer's disease.  We have carefully selected:

  • Strains and genes that are associated with Alzheimer’s disease
  • Genetic tests to validate the strains including PCR and sequencing

These sequence validated strains enable researchers to:

  • Screen for drugs with activity against Alzheimer’s disease
  • Rapidly identify impactful drugs
  • Test drug compounds on a whole organism

Model Options

STRAIN
HUMAN GENE
WORM GENE HOMOLOGUE
TYPE OF TRANSGENIC
PROTEIN ACTIVITY
WORM PHENOTYPE
ALZ PSEN1 Knock-out1 PSEN1 - 70% of all early onset Alzheimer’ssel-12Loss of Function. Improper processing of APP proteinPlaque formationEgg laying defect
ALZ MAPT KnockoutMAPTptl-1Lof - entire coding sequence is removedtau tanglesSynaptic vesicle trafficking defects
ALZ Humanized Aβ2Aβ (cleavage product of APP)N/AGain on Function. Human disease gene expressed in wormPlaque formationParalysis
ALZ Humanized MAPT3MAPTptl-1Gain of Function Addition of humanized disease genetau tanglesUncoordinated

Key Advantages of the Alzheimer’s Diesease Models

  • Ready-to-screen format (Fig. 1) enables quicker identification of drug impacts
  • Genetic mutations are validated with sequencing
  • Recommended reference strains selected for their relevance to Alzheimer’s disease
  • Consistent number of animals received
Fig1_AN87-D2_Lyso-NeuroGreen_composite

Fig 1. Day-2 ALZ PSEN1 Knock-out live C. elegans on NGM plate. This worm was dyed with both RediStain™ WormDyes  Lyso (magenta) and Neuro Green (cyan) to stain sensory neurons and apoptotic corpses in the gonad respectively.

The sel-12(ty11) mutation produces defects in vulva and neuronal development leading to a dysfunctional uterine-vulval connection and ultimately the inability to lay eggs. The worm is positioned head-down on the left and head-up on the right.

Video: Day-1 adult ALZ Humanized MAPT C. elegans in 5HT 10mM. This worm immobilized into a ScreenChip Channel expresses GFP in the pharyngeal muscles under the control of the myo-2 promoter.

Publications (Zebrafsih model)

  1. Zebrafish: an emerging real-time model system to study Alzheimer's disease and neurospecific drug discovery. Saleem, S.; Kannan, R. R. Cell death discovery, 4, 45.
    https://doi.org/10.1038/s41420-018-0109-7
  2. Brain transcriptome analysis of a familial Alzheimer's disease-like mutation in the zebrafish presenilin 1 gene implies effects on energy production. Newman M, Hin N, Pederson S, Lardelli M.  Mol Brain. 2019;12(1):43.
  3. Generation of Alzheimer's disease transgenic Zebrafish expressing human APP mutation under control of Zebrafish appb promotor. Pu YZ, Liang L, Fu AL, et al. Curr Alzheimer Res. 2017;14(6):668‐679.
  4. Utilizing zebrafish and okadaic acid to study Alzheimer's disease. Koehler D, Williams FE. Neural Regen Res. 2018;13(9):1538‐1541.

Publications (C. elegans model)

  1. Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer's disease. Kumar DK, Choi SH, Washicosky KJ, et al. Sci Transl Med. 2016;8(340):340ra72.
  2. Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease. Fang EF, Hou Y, Palikaras K, et al. Nat Neurosci. 2019;22(3):401‐412.
  3. Genetic and pharmacological discovery for Alzheimer's disease using Caenorhabditis elegans. Griffin EF, Caldwell KA, Caldwell GA. ACS Chem Neurosci. 2017;8(12):2596‐2606.

References

  1. Assessment of normal and mutant human presenilin function in Caenorhabditis elegans. Levitan D et al.  Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14940-4.
  2. Utility of an improved model of amyloid-beta (Aβ₁₋₄₂) toxicity in Caenorhabditis elegans for drug screening for Alzheimer's disease. McColl G et al. Mol Neurodegener. 2012 Nov 21;7:57.
  3. Neurodegeneration and defective neurotransmission in a Caenorhabditis elegans model of tauopathy. Kraemer BC et al. Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):9980-5. Epub 2003 Jul 18.
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