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Huichalaf, C.H., Al-Ramahi, I., Park, K.W., Grunke, S.D., Lu, N., de Haro, M., El-Zein, K., Gallego-Flores, T., Perez, A.M., Jung, S.Y., Botas, J., Zoghbi, H.Y., Jankowsky, J.L. (2019). Cross-species genetic screens to identify kinase targets for APP reduction in Alzheimer's disease.  Hum. Mol. Genet. 28(12): 2014--2029.
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Publication Type
Research paper

An early hallmark of Alzheimer's disease is the accumulation of amyloid-β (Aβ), inspiring numerous therapeutic strategies targeting this peptide. An alternative approach is to destabilize the amyloid beta precursor protein (APP) from which Aβ is derived. We interrogated innate pathways governing APP stability using a siRNA screen for modifiers whose own reduction diminished APP in human cell lines and transgenic Drosophila. As proof of principle, we validated PKCβ-a known modifier identified by the screen-in an APP transgenic mouse model. PKCβ was genetically targeted using a novel adeno-associated virus shuttle vector to deliver microRNA-adapted shRNA via intracranial injection. In vivo reduction of PKCβ initially diminished APP and delayed plaque formation. Despite persistent PKCβ suppression, the effect on APP and amyloid diminished over time. Our study advances this approach for mining druggable modifiers of disease-associated proteins, while cautioning that prolonged in vivo validation may be needed to reveal emergent limitations on efficacy.

PubMed ID
PubMed Central ID
PMC6548227 (PMC) (EuropePMC)
Associated Information

The ~70 VDRC RNAi line IDs used in this paper were obtained direct from author Ismael Al-Ramahi, and are included here as the associated file 'Al-Ramahi_2020.2.27.xlsx'.

Associated Files
File date: 2020.2.27 ; File size: 10228 ; File format: xlsx ; File name: Al-Ramahi_2020.2.27.xlsx
Other Information
Secondary IDs
    Language of Publication
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Hum. Mol. Genet.
    Human Molecular Genetics
    Publication Year
    Data From Reference
    Alleles (73)
    Genes (70)
    Human Disease Models (1)
    Insertions (1)
    Transgenic Constructs (72)