The health of neurons depends on a steady supply of trophic factors including nerve growth factor (NGF): A shortage of this salubrious peptide, or its receptor TrkA, has been implicated in the death of hippocampal and cortical neurons in Alzheimer disease. Recently, Carmela Matrone, Pietro Calissano, and colleagues of the National Research Council and the European Brain Research Institute in Rome, Italy, showed that NGF withdrawal also triggers amyloid-β (Aβ) peptide production in cultured hippocampal neurons (Matrone et al., 2008). However, the pathways linking the NGF withdrawal, Aβ production, and cell death have been unclear. In a new paper out in this week’s PNAS online, the researchers incriminate the TrkA and p75 NGF receptors in Aβ-induced cell death after NGF withdrawal. They provide evidence that an unexpected phosphorylation of TrkA, occurring hours after NGF removal, converts the receptor from a mediator of trophic support to an inducer of cell death. The conversion depends on β- and γ-secretase activation, which leads to Aβ production, and also to processing of the p75 NGF receptor to release a C-terminal fragment.

“These findings suggest that an alteration in TrkA function, probably due to anomalous p75 processing, concomitant to an increase of Aβ production, may be related to NGF signaling impairment and, in turn, to neuronal death,” Matrone wrote in an e-mail to ARF. The work also suggests a novel role for the TrkA receptor in cell death—a role previously reserved for the p75 receptor—in a system that may mimic the defects in NGF signaling in neurons in AD.

In the study, first author Matrone and colleagues looked at TrkA phosphorylation after NGF withdrawal from primary cultures of hippocampal neurons. As expected, NGF binding stimulated phosphorylation of the TrkA tyrosine kinase, which then quickly reversed once NGF was withdrawn, but after 24 hours, the researchers found, the tyrosine phosphorylation of the receptor rebounded to levels even higher than that elicited by NGF.

The delayed TrkA phosphorylation depended on the production of Aβ after NGF withdrawal, the investigators showed. First, phosphorylation was reduced in the presence of the Aβ antibody 4G8 and increased by addition of exogenous Aβ to the cells. Second, preventing Aβ production by treating cells with β- or γ-secretase inhibitors also completely blocked TrkA phosphorylation, which was linked to cell death: TrkA kinase inhibitors that blocked receptor phosphorylation also prevented cell death after NGF withdrawal or addition of Aβ. Similar effects of Aβ on TrkA signaling were recently reported (Bulbarelli et al., 2009).

The effects of NGF withdrawal on receptor phosphorylation and cell survival required both TrkA and a novel processing of p75. Reducing expression of either receptor with siRNA lowered TrkA phosphorylation and protected cells from death, while Aβ treatment or NGF withdrawal activated processing of p75 by the β- and γ-secretases, causing an increase of a p75 C-terminal fragment in the cytosol. This result echoes a recent report from Elizabeth Coulson’s lab at the University of Queensland, Brisbane, Australia, showing that Aβ activates a novel secretase-mediated processing of the p75 receptor, and that Aβ requires p75 to kill hippocampal neurons in vivo (Sotthibundhu et al., 2008). The Matrone work adds evidence for a role for TrkA in the process.

The signaling events downstream of TrkA became even more complicated. TrkA phosphorylation was associated with the phosphorylation of the Akt activator phospholipase C γ, but not activation of Akt itself. This suggests that the signals emanating from TrkA are not following the normal, trophic, route. Inhibitors of the CDK5 or src kinases, both implicated in Alzheimer pathology via Aβ processing and tau phosphorylation, prevented TrkA and phospholipase C γ phosphorylation and cell death after NGF withdrawal. The latter results supports the idea that there is an interplay between NGF signaling and amyloidogenic pathways, a connection further strengthened by the demonstration that TrkA, p75, Aβ, and a subunit of presenilin all coimmunoprecipitated from the cells. However, the work leaves up in the air the order of events, such as how Aβ production, stimulation of TrkA, processing of p75, activation of CDK5, etc., might proceed.

“This work is consistent with our and others’ findings that p75 is a mediator of Aβ-induced neuronal cell death signaling,” Coulson wrote in an e-mail to ARF. “I’m happy to see that addition of Aβ replicates our finding of increased C-terminal fragment of p75 (that can promote death) in response to endogenous or exogenous Aβ. Together, these [results] suggest that Aβ is interfering with p75 processing and therefore likely with receptor complex endocytosis and signaling.”

Coulson finds it more surprising that downregulation of TrkA also promoted survival. “The idea that TrkA signals death is novel, but the in vivo relevance and basic mechanisms remain to be determined.”—Pat McCaffrey


  1. I'm not sure the impact of β- and γ-secretase inhibitors in this system confirms a role for Aβ. The authors themselves are careful to refrain from that conclusion. Indeed, some of their data "points to the possibility that Aβ, when externally added, may activate different unknown mechanism(s) of death." It is quite likely that the relevant γ-secretase substrate here is p75 rather than APP. And though it is not clear precisely which β-secretase inhibitors were used, they all have questionable specificity; even if specific for BACE1, this enzyme has predictable activity against substrates other than APP. According to sequence requirements determined by Grüninger-Leitch et al. (2002), an intriguing candidate is transmembrane protein 132A (aka, GRP78-binding protein), a brain protein shown to protect neuro2A cells against trophic-factor withdrawal (Oh-hashi et al., 2003). Among others is FOXO3a, recently found to be broadly neuroprotective (Mojsilovic-Petrovic et al., 2009).


    . Substrate and inhibitor profile of BACE (beta-secretase) and comparison with other mammalian aspartic proteases. J Biol Chem. 2002 Feb 15;277(7):4687-93. PubMed.

    . FOXO3a is broadly neuroprotective in vitro and in vivo against insults implicated in motor neuron diseases. J Neurosci. 2009 Jun 24;29(25):8236-47. PubMed.

    . Cloning and characterization of a novel GRP78-binding protein in the rat brain. J Biol Chem. 2003 Mar 21;278(12):10531-7. PubMed.

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Paper Citations

  1. . NGF and BDNF signaling control amyloidogenic route and Abeta production in hippocampal neurons. Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13139-44. PubMed.
  2. . TrkA pathway activation induced by amyloid-beta (Abeta). Mol Cell Neurosci. 2009 Mar;40(3):365-73. PubMed.
  3. . Beta-amyloid(1-42) induces neuronal death through the p75 neurotrophin receptor. J Neurosci. 2008 Apr 9;28(15):3941-6. PubMed.

Further Reading

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Primary Papers

  1. . Tyrosine kinase nerve growth factor receptor switches from prosurvival to proapoptotic activity via Abeta-mediated phosphorylation. Proc Natl Acad Sci U S A. 2009 Jul 7;106(27):11358-63. PubMed.