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.