Membrane‐bound β‐amyloid oligomers are recruited into lipid rafts by a fyn‐dependent mechanism

Abstract

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Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

“…In particular this includes major brain tyrosine kinases (e.g., Fyn, Src, Lck, Abl) that can bind to the PXXP motifs in the proline-rich domain of Tau through their SH3 domain ( Fig. 1, bottom; Bhaskar et al 2005;Williamson et al 2008;Ittner et al 2010). …”

“…Unlike MAP2, which has a recognition site for the RII subunit of PKA, Tau does not have a well-characterized binding site for kinase-regulatory proteins. The best-defined kinase interaction sites are the PXXP motifs in the proline-rich domain that can bind to SH3-containing proteins including tyrosine kinases Fyn, Src, or Lck (Reynolds et al 2008;Williamson et al 2008). Thus, overexpression of Tau fragments lacking the repeat domain, which stay in the cell body because they cannot be sorted into the axon, also leads to a local accumulation of Fyn , and presumably other SH3-domain proteins.…”

“…A role for Tau -Fyn interactions has been postulated for oligodendrocytes where the complex is transported into cell processes in a MT-dependent manner and is required for myelination (Belkadi and LoPresti 2008;Klein et al 2002). In neurons, the Tau-Fyn complex becomes enriched in lipid rafts upon exposure to Ab (Williamson et al 2008). An analogous cotransport of Tau with Fyn has recently been postulated for neuronal dendrites and spines, enabling Fyn to phosphorylate NMDA receptors and to mediate Ab-induced excitotoxicity.…”

“…The emerging picture is that a small fraction of cellular Tau binds to the membrane through membrane-associated proteins, for example, annexins or proteins of lipid rafts (Williamson et al 2008;GauthierKemper et al 2011). Independently of that, Tau can also interact with anionic lipid bilayers and micelles, at least in vitro (Chirita et al 2003;Elbaum-Garfinkle et al 2010).…”

An in vitro model for synaptic loss in neurodegenerative diseases suggests a neuroprotective role for valproic acid via inhibition of cPLA2 dependent signalling

“…The recruitment of signalling proteins to specific compartments is an emerging concept in the regulation of cell activation. The observations that Aβ is found within lipid rafts (Williamson et al, 2008) and the Aβ-induced activation of cPLA2 is cholesterol sensitive (Bate and Williams, 2007) suggests that the formation of specific lipid rafts is necessary for Aβ-induced activation of cPLA2 and synapse degeneration. Critically, pre-treatment with VPA or PIA reduced the Aβ-induced translocation of cPLA2 to rafts.…”