Rudolf Blöchl
Since
publication of the hypothesis in autumn 2008 new data have been
published that affect this hypothesis and that have been interpreted in
the updated overview of the hypothesis at www.abeta-p75.de. Two of
these
reports (Bulbarelli et
al., 2009, and Matrone
et al., 2009) give rise to an extension of the hypothesis in the sense
that Abeta may also crosslink p75 and TrkA receptors and thereby
modulate neurotrophin receptor signaling.
Bulbarelli
et al. show that administration of (proapoptotic) Abeta25-35 or
oligomeric Abeta1-42 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 GSK3beta
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 defence mechanism against
increased Abeta or part of a proapoptotic response to Abeta. Matrone
et al. found in NGF-dependent cultures of hippocampal neurons that
NGF withdrawal causes an increase in Abeta that leads to proapoptotic
signaling of TrkA. Their results also indicate a direct interaction
of TrkA, p75 and Abeta and a role of multiprotein TrkA-p75 complexes
in this apoptosis. According to their interpretation, NGF withdrawal
causes an imbalance of beta and gamma secretase activities that
induces apoptosis by increased levels of Abeta and of p75 fragments
and by Abeta- and p75-mediated TrkA signaling. The model presented
here suggests that crosslinking of TrkA and p75 by increased
Abeta,
transactivation of TrkA by an associated p75 signaling complex and
suppression of prosurvival TrkA signaling by p75-induced ceramide
accumulation may underlie the observed proapoptotic TrkA activity.
The following considerations refer to results by Matrone et
al. if not indicated otherwise. The striking increase in Abeta upon
NGF withdrawal could in part be due to a ceasing of the inhibitory
influence of NGF-stimulated TrkA on beta cleavage of APP, and a
ceramide-dependent stimulating effect of (Abeta-)activated p75 on
this cleavage (cf. Costantini
et al., 2005,
and Puglielli et al.,
2003); since NGF
administration elevates TrkA expression (Kojima
et al., 1995) and consequently inhibition of beta cleavage by TrkA,
Abeta production might react to NGF withdrawal with a rebound effect.
The findings that the increased association of TrkA with p75FL
(full-length p75) and p75CTF (the C-terminal fragment that is
generated by alpha cleavage of p75) depends on Abeta, and that p75
coprecipitates with TrkA and p75CTF with Abeta, hint that endogenous
Abeta could induce such complex formation by direct intervention.
Zampieri and Chao (2006)
supposed that the
association of p75 with TrkA might be mediated by sequences in the
stalk domain of p75 and that these sequences "might also play a
pivotal role in controlling the association of p75 with its
co-receptor partners", while Jung
et al.
(2003) reported that TrkA-p75 association requires the transmembrane
domain of p75; TrkB-p75 association, on the other hand, might be
independent of the transmembrane domains of TrkB and p75 (Bibel
et al., 1999). Evidence presented by the Abeta-crosslinker-hypothesis
shows that Abeta has - in addition to the known binding site in the
neurotrophin-binding region of p75 - a second binding site on p75 in
the
juxtamembrane stalk region which probably extends into the
transmembrane domain and overlaps the section between the alpha and
gamma cleavage sites. This "stalk binding site" for Abeta might
reconcile the results by Jung
et al. (2003) with
those by Zampieri and Chao
(2006): if it
mediates p75 cooperation with e.g. TrkA then its intersections with
the stalk or the transmembrane domain may also do so although less
efficiently. Taken together, the given arguments point to a
crosslinking of TrkA and p75 by Abeta (non-beta-sheet oligomers),
which obviously should depend on the level of Abeta; increased Abeta
oligomers might saturate p75 receptors at this binding site and thus
facilitate complex formation. However, crosslinking by Abeta need not
be the only way of TrkA-p75 association since a ternary complex
consisting of TrkA, Kidins220/ARMS and p75 has been described (Chang
et al., 2004). If crosslinking of TrkA and p75 really occurs then it
apparently does not inhibit cleavage of (activated) p75CTF by gamma
secretase as data by Matrone et al. on p75ICD (the intracellular domain
of p75) and presenilin 1 prove. In contrast, the binding of
unsuitable aggregate species of Abeta to the stalk binding site of
p75, resulting from administration or extended overproduction of
Abeta, could impair the interaction between p75 and gamma secretase
and cause accumulation of p75CTF upon p75 activation and alpha
cleavage of p75 (cf. Sotthibundhu
et al.,
2008). A binding site for Abeta on TrkA implies the possibility that
binding of unsuitable Abeta aggregates might hamper TrkA activation
by NGF and lead to reduced TrkA expression (cf. Costantini
et al., 2005).
Matrone et al. report an almost total
interruption of Akt phosphorylation upon NGF withdrawal, which
indicates that the survival-promoting TrkA and p75 pathways, in
particular the PI3K/Akt pathway, are inhibited. Part of this apparent
inhibition might be due to coupling of Akt to increased TrkA
multiprotein complexes and gradual dephosphorylation; in addition,
high TrkA together with rising Abeta might favor TrkA-p75 association
at the expense of (hypothetical) other cooperations of p75 and thus
further weaken neuroprotective signaling of p75. However, since the
PI3K/Akt pathway is inhibited by elevated cytosolic ceramide (cf.
e.g. Arboleda et al.,
2009), and since the
cell death observed by Matrone et al. depends on Abeta and p75 and
both Abeta- and p75-induced apoptosis requires the activation of a
sphingomyelinase-ceramide pathway (Malaplate-Armand
et al., 2006, and Brann et
al., 2002), Abeta
should inhibit Akt phosphorylation mainly through activation of p75
and ensuing
ceramide production. p75 is also responsible for TrkA phosphorylation
after NGF withdrawal as partial silencing of p75 RNA largely reduces
cell death and TrkA phosphorylation. CDK5 and Src kinases participate
in this phosphorylation, and the same Src kinases that according to
Egert et al. (2007) mediate p75
phosphorylation
by Abeta aggregates or by NGF might also phosphorylate p75-associated
TrkA. CDK5 activation by Abeta, which contributes to Abeta-induced
pathology,
can be prevented by synthetic non-peptide ligands of p75 (Yang
et al., 2008) and might therefore be connected with Abeta-induced p75
signaling. By facilitating p75-induced TrkA phosphorylation,
TrkA-p75CTF and TrkA-p75FL complexes should be crucial to the
reported proapoptotic activity of TrkA. Under the conditions of
elevated ceramide and inhibited PI3K/Akt pathway, activated
p75-associated TrkA could support and amplify proapoptotic p75
signaling, presumably through the Ras/Rac/JNK pathway (cf. Egert
et al., 2007, and Harrington
et al., 2002).
As partial silencing of TrkA RNA largely diminishes cell death, the
NGF-induced rise in TrkA receptors prior to NGF withdrawal is
critical for the observed apoptosis. This suggests that higher TrkA
expression may lead to cell degeneration or cell death even at
otherwise non-apoptotic Abeta concentrations when Abeta-activated
TrkA-p75 complexes tip the balance in favor of apoptosis. In living
tissue, NGF and TrkA expression might be upregulated in response to
rising, non-lethal Abeta concentrations (cf. Bulbarelli
et al.) and counteract Abeta (and perhaps cause neuronal hypertrophy
as reported by Iacono et al.
(2008)), but when
Abeta further increases it might crosslink a growing proportion of
TrkA receptors with p75 and successfully compete with NGF for
activation of TrkA-p75 complexes. In this case, it would be
interesting to know if significant Abeta-induced TrkA transactivation
can
downregulate TrkA.
At physiological Abeta levels and generally
as long as the p75-induced ceramide signal does not suppress the
PI3K/Akt pathway, which is also induced by p75 (Roux
et al., 2001), Abeta stimulation of p75 and TrkA-p75 complexes should
have neurotrophic and neuroprotective consequences similar to NGF
stimulation (cf. Susen and Blöchl,
2005).
For the overall effect of Abeta or NGF stimulation, the (possibly
predominant) contributions of other cooperations of p75 and of
non-associated p75 and TrkA - which depend on the ratio TrkA:p75 -
have to be taken into account, too. NGF-mediated activation of TrkA
and TrkA-p75 complexes can suppress ceramide production by
NGF-stimulated or transactivated p75 through a TrkA-induced
PI3K/PKC-dependent mechanism (Plo
et al., 2004) if
TrkA and TrkA-p75 complexes prevail over independent p75. Then
NGF-induced signaling of TrkA-associated p75 should support and
amplify the neurotrophic and neuroprotective TrkA signaling (cf. Epa
et al., 2004) since ceramide is critical for p75-induced apoptosis
(Brann et al., 2002).
Speculative
considerations and a few clues suggest, that the p75-binding site of
a crosslinking Abeta oligomer might essentially be attributable to an
N-terminal section of the Abeta sequence, and the TrkA-binding site
mainly to part of the C-terminal rest; the hypothetical binding site
of TrkA for Abeta might be found within the transmembrane domain of
TrkA and its immediate vicinity. Such binding sites might explain
NGF-independent TrkA activation upon Abeta administration in the
experiments by Bulbarelli
et al.: short
stacks of beta-sheet Abeta25-35 or Abeta1-42, presenting symmetric
binding sites at their ends, might homodimerize TrkA while
non-beta-sheet Abeta1-42 oligomers might cause TrkA-p75 association
and activation as described above. Bulbarelli et al. discussed
membrane effects of Abeta as a
possible cause of NGF-independent TrkA activation.
The presented arguments
suggest that Abeta can crosslink TrkA receptors with p75, that p75
stimulation by Abeta induces activation of p75-associated TrkA, and
that suppression of the survival-promoting PI3K/Akt pathway by
p75-induced ceramide accumulation causes p75-associated TrkA to
support and amplify proapoptotic signaling of p75. Complexes of TrkA
and p75 receptors can serve both trophic and neuroprotective ends or
negative growth control and apoptosis, depending on mutual adjustment
of receptor conformation and signaling, on the balance or imbalance
of the PI3K/Akt and ceramide pathways, and on the stimulation
parameters. By altering, integrating and synergizing signaling
properties of TrkA and p75, these complexes can optimize and amplify
certain signal transductions and in many cases tip the scales in
favor of trophic or negative processes. If Abeta regulates their
formation and also crosslinks p75 receptors with other cooperation
partners then it could substantially modulate neurotrophin receptor
signaling and affect many cellular processes; such crosslinking,
however, would also sensitize the neurotrophin receptor system to
excess Abeta, as the report by Matrone et al. demonstrates.
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