Cross-species genetic screens to identify kinase targets for APP reduction in Alzheimer's disease
Year: 2019
Type: article
Abstract: 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.
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddz034
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Multidisciplinary Training in Brain Disorders and Development, Genetic Screens to Identify Targets that Regulate Amyloid Precursor Protein (APP), Deconstructing the pathogenic effect of APP in memory circuits, Deconstructing Entorhinal Degeneration and Repair in Alzheimer's Disease, G9000138680, G9000323922, Baylor College of Medicine Cancer Center - Cancer Center Support Grant, Behavioral and cell-based complementary screens to identify druggable targets modulating tau protein levels
OpenAlex ID: W2912911406