Overcoming barriers and thresholds – signaling of oligomeric Aβ through the prion protein to Fyn

Abstract

Evidence has been mounting for an involvement of the prion protein (PrP) in a molecular pathway assumed to play a critical role in the etiology of Alzheimer disease. A currently popular model sees oligomeric amyloid β (oAβ) peptides bind directly to PrP to emanate a signal that causes activation of the cytoplasmic tyrosine kinase Fyn, an essential player in a cascade of events that ultimately leads to NMDA receptor-mediated excitotoxicity and hyper-phosphorylation of tau. The model does not reveal, however, how extracellular binding of oAβ to PrP is communicated across the plasma membrane barrier to affect activation of Fyn. A scenario whereby PrP may adapt a transmembrane topology to affect Fyn activation in the absence of additional partners is currently not supported by evidence. A survey of known candidate PrP interactors leads to a small number of molecules that are known to acquire a transmembrane topology and understood to contribute to Fyn activation. Because multiple signaling pathways converge onto Fyn, a realistic model needs to take into account a reality of Fyn acting as a hub that integrates signals from multiple inhibitory and activating effectors. To clarify the role of PrP in oAβ-dependent excitotoxicity, future studies may need to incorporate experimental designs that can probe the contributions of Fyn modulator pathways and rely on analogous readouts, rather than threshold effects, known to underlie excitotoxic signaling.

An isoform‐specific role of FynT tyrosine kinase in Alzheimer's disease

“…; Wang et al . ; Xia and Götz ). However, to the best of our knowledge, no study has focused on the role of Fyn in astrocytic activation in association with AD.…”

ApoE and Aβ in Alzheimer’s Disease: Accidental Encounters or Partners?

“…LRP1 also indirectly interacts with Aβ through its ligands, including apoE, α2-macroglobulin (Narita et al, 1997) and prion proteins (Rushworth et al, 2013). It was shown that cellular prion protein (PrP c ) mediates Aβ oligomer binding to the cell surface (Lauren et al, 2009; Wang et al, 2013), where LRP1 functions as a co-receptor of PrP c (Rushworth et al, 2013). Furthermore, it is important to note that LRP1 and HSPG can form immunoprecipitable complexes at the cell surface, which might further regulate the metabolism of apoE and Aβ (Wilsie and Orlando, 2003).…”

Neurological dysfunctions associated with altered BACE1‐dependent Neuregulin‐1 signaling

“…BACE, known as b-site amyloid precursor protein (APP) cleaving enzyme (Yan and Vassar 2014), is a membraneanchored aspartyl protease required for the generation of bamyloid peptides (Ab) (Hussain et al 1999;Sinha et al 1999;Vassar et al 1999;Yan et al 1999;Lin et al 2000). In brains of patients with Alzheimer's disease (AD), abnormally accumulated Ab tends to oligomerize, aggregate and induce synaptic dysfunction and memory loss (Walsh et al 2002;Gong et al 2003;Haass and Selkoe 2007;Wang et al 2013;Price et al 2014;Tu et al 2014). Ab refers to peptide mixtures comprised of variants 38 to 43 amino acids long, but 40 and 42 (Ab40 and Ab42) are the most common.…”