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| 2008 | 107 | 1294–1303

doi: 10.1111/j.1471-4159.2008.05690.x

F. Hoffmann-La Roche Ltd., CNS Preclinical Research, Grenzacherstrasse 124, 4070 Basel, Switzerland

Abstract Degeneration of cholinergic basal forebrain neurons (CBFN) is a hallmark in the pathology of Alzheimer’s disease (AD). Critically depending upon the neurotrophic support through nervegrowth factor (NGF), CBFN in the AD brain face elevated concentrations of the pro-form of NGF (proNGF) and suffer from an imbalance between TrkA and p75NTR expression. Research for the underlying mechanisms of CBFN death suggested a pro-apoptotic activity of proNGF. However, this finding could not be confirmed by all investigators and other studies even observed a neurotrophic function of proNGF. In thepresence of these controversial findings we investigated the activity of proNGF in PC12 cells with specific emphasis on its neurotoxic versus neurotrophic action. In this study, we

show that proNGF can mediate TrkA receptor signaling directly, yet in the manner of a partial agonist with a lower maximum activity than NGF. A pro-apoptotic activity of proNGF could not be confirmed in our cellularsystem. Interestingly and surprisingly, pre-incubation with proNGF at low, sub-active concentrations inhibited TrkA-mediated neurotrophic NGF signaling in PC12 cells. Our data support a novel hypothesis for the role of elevated proNGF levels in CBFN pathology in AD. Thus, proNGF can indirectly contribute to the slow neurodegeneration in AD by reducing NGF-mediated trophic support. Keywords:Alzheimer’s disease, neurotrophin, p75 receptor, partial agonist, ProNGF, tyrosine kinase receptor. J. Neurochem. (2008) 107, 1294–1303.

Alzheimer’s disease (AD) is a neurodegenerative disorder clinically characterized by progressive cognitive decline, and pathologically by the presence of senile plaques, neurofibrillary tangles, degeneration of synapses and dendrites accompanied by neuronal loss. Damageand reduction of cholinergic basal forebrain neurons (CBFN) appears to be responsible for alterations in cognitive and attentional behaviors in AD patients (Coyle et al. 1983). This neuronal loss has been associated to the lack of trophic support by nerve growth factor (NGF) (Levi-Montalcini and Angeletti 1963) playing a major role for CBFN survival (Williams et al. 1986; Chen et al. 1997; Countsand Mufson 2005). The trophic action of NGF is mediated through binding to a specific tyrosine receptor kinase (TrkA) resulting in receptor internalization, retrograde axonal transport (Ginty and Segal 2002) and signaling through mitogen-activated protein kinase (MAPK) (Watson et al. 2001) and Akt pathways (Kuruvilla et al. 2004). NGF downstream signaling via TrkA is therefore linked to neuronaldifferentiation and survival. In contrast, NGF also binds to the pan neurotrophin receptor p75NTR that can cause opposing effects likely to depend upon the physiological state of the cell. In the absence of co-expressed TrkA, p75NTR can mediate cell death (Rabizadeh et al. 1993; Cotrina et al. 2000; Friedman 2000) believed to involve the

activation of Jun N-terminal kinase (Bhakar et al. 2003;Gentry et al. 2004). In the presence of TrkA, p75NTRassociated cell survival was observed (Yoon et al. 1998; Kuruvilla et al. 2004) by activation of nuclear factor jB (NFjB) (Khursigara et al. 2001; Wooten et al. 2001). For the most part though, p75NTR mediated apoptosis was reported. In summary, a balance between neurotrophic and neurotoxic activity of NGF appears to define the fate of CBFN.Interestingly, cortical TrkA levels are decreased whereas p75NTR expression is unchanged in AD patients (Mufson et al. 1997; Counts et al. 2004; Ginsberg et al. 2006). Furthermore, elevated concentrations of proNGF have been described in the AD brain (Fahnestock et al. 2001). This suggests a shift of the equilibrium of p75NTR- and TrkAmediated NGF activity on CBFN in AD brains.
Received June 2, 2008;...
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