Updated 2 February 2010

Trained originally as a mathematician and biologist, Rudolf Bloechl is an independent investigator in Germany. He has performed laboratory research, and has been involved with research into neurotrophins and their receptors for many years. Bloechl invites the Alzheimer disease research community to test his hypothesis about a role of the Aβ peptide in crosslinking the neurotrophin receptor p75 with APP and other proteins. See abstract below.

Aβ-mediated Crosslinking May Regulate TrkA-p75 Association and Cooperations of p75 With APP, Prion, and Synuclein
By Rudolf Bloechl, independent investigator, Germany

The text is also available as a PDF file at Rudolf Blöchl’s website.

The Aβ-crosslinker-hypothesis presents evidence for a previously unknown binding site for Aβ on the stalk domain of p75 and proposes that Aβ can crosslink p75 with proteins such as APP, prion and alpha-synuclein and thereby mediate direct, neurotrophic and neuroprotective cooperations of p75 with these proteins. This crosslinking mechanism, however, would also permit the binding of pathological aggregate species of various amyloidogenic proteins to the stalk of p75 and lead to detrimental effects of p75 in different degenerative diseases; such effects might be reduced or prevented by derivatives of the stalk binding site of p75 for Aβ. Since publication of the hypothesis in autumn 2008, new data have been reported that affect this hypothesis and that have been interpreted in an updated overview of the hypothesis. Two of these reports (Bulbarelli et al., 2009; Matrone et al., 2009) give rise to an extension of the hypothesis in the sense that Aβ may also crosslink p75 and TrkA receptors and thereby modulate neurotrophin receptor signaling.

Bulbarelli et al. show that administration of (pro-apoptotic) Aβ25-35 or oligomeric Aβ1-42 to primary cultures of hippocampal neurons produces a temporary and marked elevation of NGF release, TrkA protein, NGF RNA and TrkA RNA, and of TrkA, Akt, and GSK3β phosphorylation; the observed TrkA activation is largely NGF-induced and partly independent of NGF. The investigation raised the question whether NGF and TrkA upregulation might be a defense mechanism against increased Aβ or part of a pro-apoptotic response to Aβ. Matrone et al. found in NGF-dependent cultures of hippocampal neurons that NGF withdrawal causes an increase in Aβ that leads to pro-apoptotic signaling of TrkA. Their results also indicate a direct interaction of TrkA, p75, and Aβ and a role of multiprotein TrkA-p75 complexes in this apoptosis. According to their interpretation, NGF withdrawal causes an imbalance of β and gamma-secretase activities that induces apoptosis by increased levels of Aβ and of p75 fragments and by Aβ- and p75-mediated TrkA signaling. The model presented here suggests that crosslinking of TrkA and p75 by increased Aβ, transactivation of TrkA by an associated p75 signaling complex and suppression of pro-survival TrkA signaling by p75-induced ceramide accumulation may underlie the observed proapoptotic TrkA activity.