. Selective vulnerability in Alzheimer's disease: amyloid precursor protein and p75(NTR) interaction. Ann Neurol. 2009 Mar;65(3):294-303. PubMed.


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  1. The issue of selective neuronal vulnerability is critical to understanding the basic pathophysiology of AD. Bredesen and colleagues have taken an important step in exploring this issue in the basal forebrain cholinergic system. It will be extremely interesting to determine in future study whether the interactions reported here are applicable to the brain stem cholinergic system, which does not lose neurons in AD, as well as to other examples of differential vulnerability such as hippocampal CA1 versus CA3.

  2. The paper reports a direct interaction of p75 and APP that crucially involves the first N-terminal 16 amino acids of Aβ within APP and that is negatively influenced by Aβ and nerve growth factor NGF. p75 expression diminishes the production of neurotrophic sAPPα and transcriptional effects of Fe65-APP interaction. Furthermore, in rat neuroblastoma B103 cells cotransfected with p75 and APP more cell death and higher caspase-3 activity can be observed than in cells expressing p75 or APP alone. The authors conclude that p75-APP interaction reduces the trophic effects of APP and leaves neurons with coexpression of p75 and APP vulnerable to Alzheimer disease, in particular, the cholinergic neurons of the basal forebrain.

    The finding of the interaction between p75 and APP and the identification of the probable binding site on APP should be most valuable for the research into the role of p75 in both neuronal activity and neurodegenerative processes. Though the paper concentrates on possible detrimental effects of this interaction, the finding also opens the possibility of studying physiological functions of p75-APP interaction. Some interpretations by the authors, however, are not convincing.

    1. The results from the used methods suggest that p75 and APP interact directly but they do not prove it. Since the C99 fragment of APP (in contrast with C83) interacts as well with p75 as full-length APP, the first 16 amino acid residues of Aβ in APP are essential for p75-APP interaction, and the interacting site on p75 should bind this Aβ segment. The known Aβ binding site within the neurotrophin-binding domain of p75 is not likely to mediate the p75-APP interaction since in the bioluminescence resonance energy transfer (BRET) study the relatively big YFP tag attached to the N-terminus of p75 should have sterically impeded such interaction. There is evidence that the stalk domain of p75 contains a second binding site for Aβ (see Current Hypotheses: Aβ Crosslinks Neurotrophin Receptor), which in the BRET analysis could have been involved in the interaction. In the two-hybrid study both p75 binding sites for Aβ may have been able to bind the Aβ segment contained in the extracellular part of APP. In cells with endogenous Aβ, however, p75 and APP might be crosslinked by available or newly formed short Aβ oligomers via the high-affinity p75 stalk binding site for Aβ.

    2. The observed reduction of p75-APP interaction by NGF and Aβ may depend on the (unlisted) period of NGF or Aβ incubation since both proteins activate p75 and lead to proteolysis of p75 and APP. Such proteolysis may mask the true extent of p75-APP interaction upon ligand-binding and may also underlie the reduction of p75-APP interaction observed in mice with Swedish and Indiana APP mutations; Aβ is increased in these mice and may stimulate p75. In addition, endogenous and added Aβ should compete with APP for binding to the p75 stalk binding site for Aβ and thus reduce p75-APP interaction.

    3. The authors also show that p75 expression in B103 cells diminishes the production of sAPPα and increases the production of Aβ from C99 fragments of APP, and that the first effect is abolished by incubation of the cells (for 20 hours) with NGF or Aβ. p75 activation has been reported previously to regulate sAPPα shedding (Rossner et al., 1998), and the reduction of sAPPα production by unstimulated p75 could serve the regulation and amplification of neurotrophin and Aβ signaling effects by noise reduction and need not be an antitrophic effect.

    4. Activated p75 increases Aβ production by elevating BACE1 activity through ceramide (cf. Costantini et al., 2005). A sufficiently high expression of p75 and APP with corresponding Aβ production may start a vicious cycle leading to cell death through stimulation of p75 by aggregated Aβ, especially when NGF and its specific receptor TrkA are absent; stimulated TrkA slightly lowers BACE1 activity (Costantini et al., 2005) and prevents ceramide generation by p75 in TrkA-p75 complexes (Plo et al., 2004). p75 activation by aggregated Aβ might be the cause of the observed increased cell death in B103 cells transfected with p75 and APP, and the generalized conclusion that coexpression of p75 and APP triggers cell death may depend on unphysiological experimental conditions. Such coexpression is not rare and obviously does not cause apoptosis under normal conditions.

    The conclusion that the interaction between p75 and APP "shifts the effect of APP from a trophic one...to an anti-trophic one" relies mostly on data from transfected B103 cells and represents a one-sidedly negative interpretation of this interaction. There are many hints in the literature supporting the view that such an interaction may have a positive, trophic role under physiological conditions and allow a direct functional cooperation of the two proteins, e.g., in growth cones and synapses. The interaction may be mediated by Aβ oligomers via the p75 stalk binding site for Aβ that under pathological conditions could be hijacked by aggregate species of various amyloidogenic proteins binding to the p75 stalk either directly or through p75-bound Aβ. If this is correct then it is the interaction between p75 and Aβ that makes neurons vulnerable to Alzheimer's disease, and not the interaction between p75 and APP which is prevented by pathological interference with the interaction mechanism.


    . A TrkA-to-p75NTR molecular switch activates amyloid beta-peptide generation during aging. Biochem J. 2005 Oct 1;391(Pt 1):59-67. PubMed.

    . Nerve growth factor-induced protein kinase C stimulation contributes to TrkA-dependent inhibition of p75 neurotrophin receptor sphingolipid signaling. J Neurosci Res. 2004 Aug 15;77(4):465-74. PubMed.

    . p75 and TrkA receptor signaling independently regulate amyloid precursor protein mRNA expression, isoform composition, and protein secretion in PC12 cells. J Neurochem. 1998 Aug;71(2):757-66. PubMed.

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  1. Peripheral p75 Protects Against Aβ Toxicity