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The implication of SRC family kinases in Alzheimer’s disease

2020; Wiley; Volume: 16; Issue: S2 Linguagem: Inglês

10.1002/alz.038447

1552-5279

Julianne L. Beirute‐Herrera, David Diouf, Daniël L.A. van den Hove, Diego Mastroeni,

Dementia and Cognitive Impairment Research

Abstract Background Alzheimer’s disease (AD) remains as one of the major challenges for the neuroscientific community today. It affects approximately 50 million cases worldwide, with a total cost estimation of $290 billion in 2019 (Alzheimer’s Association, 2019). The pathophysiological hallmarks of AD are amyloid beta plaques (Aβ) and neurofibrillary tangles (NFTs). Nevertheless, the underlying mechanism have yet to be elucidated (Mehta et al., 2017). Recent efforts have demonstrated that non‐receptor Src‐family tyrosine kinases in AD are potential targets for therapeutic intervention and we show epigenetic mechanisms associated with the expression of non‐receptor Src‐family tyrosine kinase (e.g. methylation), as a mechanism for its dysfunction (Kaufman et al., 2015; Iatrou, Kenis, Rutten, Lunnon & van den Hove, 2017). The current project aims to investigate the proteomic, genomic and epigenomic correlation of c‐ and v‐SRC to PYK2 and Fyn in neuropathologically confirmed AD and nondemented control cases. Method Western blots, immunohistochemistry, qPCR and Methylation Specific PCR will be performed in the Medial Temporal Gyrus (MTG) of 10 AD cases in a range of disease states (Braak stage IV, V and VI) and in 10 healthy age matched controls (Braak stage 0‐II). Laser Capture Microdissection will be used prior to qPCR to select neurons and microglia. For the statistical analysis, a 2‐tail student t test and regression analysis of expression profiles will be conducted using IBM SPSS Statistics 25.0 with a significance level of >0.05 and covariates like Braak stage and gender. Results Preliminary results already showed a significant upregulation of v‐Src and Fyn in CA1 laser capture neurons in AD cases compared to controls. While immunohistochemistry shows an upregulation of the Src family kinases in the CA1 of the AD cases. We hypothesize that there is an upregulation of c‐Src, v‐Src, Fyn and PYK2 mRNA/protein levels in AD cases, which is correlated to hypomethylation in the promoter regions of the corresponding genes in AD cases. Furthermore, is expected that the same proteins interact in both microglial and neuronal cells following an equivalent pattern. Conclusion V‐Src and Fyn are upregulated in Alzheimer’s disease cases and must be considered to further study the pathophysiology of the disease.