Altered p59Fyn kinase expression accompanies disease progression in Alzheimer's disease: implications for its functional role
Introduction
Alzheimer's disease (AD), the most common neurodegenerative dementing illness affecting the elderly is characterized by progressive cognitive, behavioral and functional declines, and neuropathologically by early loss of neocortical synapses, formation of neurofibrillary tangles (NFTs), and neuritic plaques (NPs) composed of aggregated β-amyloid peptide [37]. The mechanisms leading to synaptotoxicity and neurodegeneration in AD are currently under intense investigation [26]. While several studies support the contention that early accumulation of Aβ oligomers plays a major role [15], [19], [30]; others have suggested that axonal transport and cytoskeletal alterations associated with tau hyperphosphorylation might be an important player in AD pathogenesis [3]. Both scenarios involve alterations in common and divergent signaling pathways that otherwise are critical mediators of synaptic functioning, neuronal survival and cell death. Among them, considerable interest have emerged in recent years on the potential role of the Fyn signaling pathway in AD, because Fyn is activated by Aβ and cells lacking this pathway are resistant to Aβ toxicity [18]. The Fyn proto-oncogene encodes a 59 kDa membrane-associated, non-receptor tyrosine kinase that, through tyrosine phosphorylation of target substrates, is involved in modulating key signal transduction processes in neurons, glia and oligodendrocytes [13], [32]. Its activity is regulated by phosphorylation/dephosphorylation and proteolytic cleavage [13], [25]. Structurally similar to Src kinase, it comprises three domains, SH1, SH2, SH3 and an amino-terminal myristolation anchor which is essential for function [13]. Studies have demonstrated that, because of myristolation, the majority of cellular Fyn kinase is localized to membrane fraction, with a small transient pool in cytosol [41]. Fyn participates at focal adhesion complexes, by associating with focal adhesion kinase (FAK) and phosphorylating FAK-binding sites, which can activate signaling pathways regulating synaptic functioning and cell survival [8]. Recent studies have shown that Fyn is also activated by both Aβ peptides (i.e. Aβ 1–42, Aβ 25–35) [29], [42], [45] and especially, by Aβ oligomers such as amyloid-derived diffusible ligands (ADDLs) [18]. Although, the receptor involved is currently unknown, Aβ-induced Fyn activation results in rapid Fyn association with FAK and phosphorylation of the Y925 residue on FAK, leading to activation and amplification of subsequent activation of downstream events [42], [45]. In addition, activated Fyn can phosphorylate tyrosine residues on tau [21], which may also be important in promoting abnormal tau phosphorylation and aggregation. Moreover, Fyn can also rapidly activate glycogen synthase kinase 3-β (GSK3-β), leading to increased tau phosphorylation [23]. Taken together, these studies support the possibility that the Fyn signaling pathway might play an important role in the pathogenesis of AD by mediating Aβ toxicity and NFT formation. However, at the present time, only a few studies are available which describe the alterations in Fyn in AD [35]. In this context, the main objective of the present study was to better understand the patterns of Fyn expression in control and AD brains and its relationship with markers of neurological impairment and neurodegeneration.
Section snippets
Methods
A total of 18 autopsy cases were included for the present study. The summary of the clinico-pathological characteristics of the subjects is presented in Table 1, and the their ages at death and post-mortem intervals are shown in Table 2. The subjects in this study included cases from a consecutive autopsy series of demented patients followed during life at the University of California, San Diego (UCSD) Alzheimer's Disease Research Center (ADRC). The study was carried out according to ethical
Fyn levels are altered in AD
By Western blot, in the MF cortex of the control cases, Fyn immunoreactivity was detected as a single band at an approximate molecular weight of 59 kDa, that was more abundant in the insoluble than in the soluble fraction (Fig. 1A). In AD, levels of Fyn immunoreactivity increased in the insoluble (Fig. 1, Fig. 2A) and decreased in the soluble fraction (Fig. 1, Fig. 2B). This shift in Fyn immunoreactivity from the soluble to the insoluble fraction was more prominent as the severity of AD
Discussion
The present study showed that in AD there is a shift in Fyn compartmentalization from the soluble to the insoluble fraction, with a corresponding change from synaptic colocalization in normal brain to colocalization with tau in AD brain. The non-ionic detergent-insoluble fraction represents cytoskeletal, highly insoluble, and some membrane components, whereas the detergent-soluble fraction largely consists of both cytosolic and loosely membrane-attached molecules. Since Fyn immunoreactivity in
Acknowledgements
This work was supported by NIH grants P50 AG05131 (to LT), AG18440 (to EM), and by training grant AG00975 (to GJH).
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2020, Journal of Biological ChemistryCitation Excerpt :Furthermore, in the P301L transgenic mouse model, Vega et al. (70) showed that Tau phosphorylation at residues Tyr-197 and Tyr-394 correlated with the formation of Tau aggregates and occurred concurrently with serine and threonine phosphorylation (detected by PHF1 antibody at residues Ser-396/Ser-404 and by CP13 at residues Ser-202/Thr-205) known to be implicated in AD pathogenesis (70). Moreover, two tyrosine kinases, Fyn and c-Abl, which are known to phosphorylate Tau, have been shown to co-localize with Tau in NFTs (18, 72). Interestingly, treatment with Aβ increased the activity of both kinases and led to a subsequent increase in Tau tyrosine phosphorylation and cell death, which could be prevented by treatment with tyrosine kinase inhibitors (73).