Isoform‐specific upregulation of FynT kinase expression is associated with tauopathy and glial activation in Alzheimer's disease and Lewy body dementias

Abstract

Cumulative data suggest the involvement of Fyn tyrosine kinase in Alzheimer's disease (AD). Previously, our group has shown increased immunoreactivities of the FynT isoform in AD neocortex (with no change in the alternatively spliced FynB isoform) which associated with neurofibrillary degeneration and reactive astrogliosis. Since both the aforementioned neuropathological features are also variably found in Lewy Body dementias (LBD), we investigated potential perturbations of Fyn expression in the post-mortem neocortex of patients with AD, as well as those diagnosed as having one of the two main subgroups of LBD: Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB). We found selective upregulation of FynT expression in AD, PDD, and DLB which also correlated with cognitive impairment. Furthermore, increased FynT expression correlated with hallmark neuropathological lesions, soluble β-amyloid, and phosphorylated tau, as well as markers of microglia and astrocyte activation. In line with the human post-mortem studies, cortical FynT expression in aged mice transgenic for human P301S tau was upregulated and further correlated with accumulation of aggregated phosphorylated tau as well as with microglial and astrocytic markers. Our findings provide further evidence for the involvement of FynT in neurodegenerative dementias, likely via effects on tauopathy and neuroinflammation.

Pharmacological Modulators of Tau Aggregation and Spreading

“…Thus, another possible strategy to counteract tau aggregation may be by decreasing hyperphosphorylation by acting on kinases. Amongst these, inhibition of tyrosine kinases has especial relevance, as it leads to the progression of the disease in AD and Parkinson's disease (PD) [264,265]. In fact, tau has 5 tyrosine residues: 18,29,197,310,and 394.…”

“…In recent years, several anticancer drugs have been repurposed for the study of their effects in neurodegenerative diseases. These drugs act on different tyrosine kinases showing effects in different pathologies such as AD, PD, stroke, spinal cord injury, and multiple sclerosis [264,265,[267][268][269][270]. Among these drugs nilotinib, dasatinib, vatalanib, and imatinib have shown promising results.…”

Establishing a competing endogenous RNA (ceRNA)-immunoregulatory network associated with the progression of Alzheimer’s disease

“…The GSE157239 miRNA dataset (public on Oct 14, 2020), including 8 AD samples and 8 normal samples, was analyzed. The lncRNA and mRNA datasets were obtained from GSE122063 (14) and GSE150696 (15). The GSE122063 dataset was used as the training set (public on Apr 23, 2019) and contains 56 AD samples and 44 normal samples.…”

“…According to the theory that lncRNA acts as a miRNA sponge to influence miRNA and regulate mRNA expression (14), a ceRNA network was constructed. During the construction of the network, the expression of lncRNAs should be negatively correlated with the expression of miRNAs and positively correlated with mRNA expression (15). The mRNAs related to the DEmiRNAs in GSE120584 dataset were identified through the miRTarbase and starBase database.…”

Tandem Mass Spectrometry as Strategy for the Selective Identification and Quantification of the Amyloid Precursor Protein Tyr682 Residue Phosphorylation Status in Human Blood Mononuclear Cells

“…Others have previously described a different involvement of Fyn in AD by increasing tau phosphorylation or triggering Aβ oligomer neurotoxicity mechanisms [ 19 , 20 , 21 , 22 , 23 , 24 ]. Recently, a Fyn upregulation in microglia cells of AD patients has been reported that precedes Aβ accumulation in neurons and contributes to neuroinflammation-associated synaptic dysfunction and neuronal damage [ 25 , 26 ].…”