. In vivo restoration of physiological levels of truncated TrkB.T1 receptor rescues neuronal cell death in a trisomic mouse model. Neuron. 2006 Jul 6;51(1):21-8. PubMed.

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  1. I think this study by Salehi and colleagues complements our work. If anything, the two studies combined stress once again the relevance of neurotrophin supply/signaling in supporting neuronal survival and function. What I find intriguing is that the two papers describe different mechanisms by which alterations in neurotrophin signaling can cause neuronal cell death, depending on the specific brain cell type affected. For example, Salehi et al. report that disrupted retrograde transport of NGF to the basal forebrain cholinergic neurons (BFCNs) causes degeneration of these neurons (I would like to note that BDNF is not a major signaling molecule in this neuronal cell population, which is why Salehi et al. find that the retrograde transport of BDNF and NT3 is below the limits of detection with the methodology used in their study). We find that an impairment of TrkB signaling causes cell death in cortical and hippocampal neurons, two cell populations that are responsive to BDNF and in which TrkB receptor isoforms alterations have been already described in Alzheimer disease (AD). As you know, all cell populations described in the two studies (BFCNs, cortical and hippocampal neurons) are affected in AD. Thus, these papers suggest that different cell populations in the brain may be affected by different genetic insults, and alternative mechanisms should be taken into account when considering therapies.

    View all comments by Lino Tessarollo
  2. The articles by Dorsey and colleagues and Mobley's group (see Salehi et al., 2006) are particularly relevant to recent findings that our group has generated using human autopsy material to investigate the neurobiological mechanisms underlying cholinotrophic basal forebrain dysfunction during the progression of AD (see review by Counts and Mufson, 2004). Findings derived from autopsy material harvested from people with a premortem clinical diagnosis of non-cognitive impairment, mild cognitive impairment, and AD revealed that subtle alterations or shifts in the balance between proNGF and the high-affinity TrkA receptor for NGF may play a crucial role in the survival of cholinergic neurons during the progression of AD. Shifts in the balance between NGF and its high-affinity receptor may dysregulate pro-survival and initiate apoptotic signaling leading to cholinergic basal forebrain neuronal death. The findings of Dorsey et al. suggest that relatively small imbalances in the physiological levels of TrkB receptor isoforms affect neuronal survival by altering BDNF-induced pro-survival signaling. Together, these findings suggest that the success of exogenous neurotrophin therapy for neurological diseases such as AD may depend upon a fine balance between neurotrophin and receptor interactions.

    Several years ago, it was demonstrated that there is a reduction in retrogradely transported NGF within cholinergic neurons of the nucleus basalis in AD (Mufson and Kordower, 1997). The article by Salehi et al. provides information that APP acts to reduce the retrograde transport of NGF in the cholinergic cortical projection neurons, a process important for their survival and relevant to their selective vulnerability in AD. Moreover, this study links the amyloid hypothesis to cholinergic basal forebrain degeneration and their ultimate demise in AD.

    Together, these observations provide evidence of the complex nature of neurotrophin/receptor as well as defects in neurotrophin retrograde transport as putative functional deficits which ultimately play a role in neuronal survival and death in various disease states. Interestingly, Costantini et al. (2005) showed that a TrkA-to-p75NTR molecular switch activates amyloid-β expression during aging. This novel information demonstrates that subtle shifts in neurotrophin receptor balance not only can affect neuron survival in neurological disease but also during the normal aging process.

    References:

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

    . The role of nerve growth factor receptors in cholinergic basal forebrain degeneration in prodromal Alzheimer disease. J Neuropathol Exp Neurol. 2005 Apr;64(4):263-72. PubMed.

    . In vivo restoration of physiological levels of truncated TrkB.T1 receptor rescues neuronal cell death in a trisomic mouse model. Neuron. 2006 Jul 6;51(1):21-8. PubMed.

    . Nerve growth factor in Alzheimer's disease: defective retrograde transport to nucleus basalis. Neuroreport. 1995 May 9;6(7):1063-6. PubMed.

    . Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration. Neuron. 2006 Jul 6;51(1):29-42. PubMed.

  3. NGF has a potent effect on cholinergic neurons in the basal forebrain, which are prone to degeneration in AD. The idea that NGF dysfunction is involved in AD has been around for some time, but it has never been taken seriously because of the prominence of the “Aβ” hypothesis. Now Mobley and colleagues show that APP acts to reduce the retrograde transport of NGF in these cholinergic neurons, a process that might be important for their survival. The significance of the work by Mobley et al. is that they provide a mechanistic link between APP and NGF signaling in the basal forebrain neurons, therefore putting NGF back into the center stage of the AD field. The immediate task now is to test whether this works in an AD model.

    The functional role of TrkB.T1, which is highly expressed in the brain, has been puzzling for some time now. One idea is that T1 has no function by itself, but prevents locally secreted BDNF from diffusion to distant places, and therefore ensures its local action. Another idea is that T1 can actually signal in glial cells in an unconventional way, but this idea is largely based on cell culture work, and there is no evidence that this works in vivo. The work of Tessarollo et al. sheds new light on the function of T1, using in vivo genetic approaches. They show that restoration of the physiological level of T1 by gene targeting rescues neuronal death in trisomy 16 mouse. Interestingly, T1 appears to affect selectively the Akt pathway, which is critical for neuronal survival. Given that the main function of BDNF in the brain is for synaptic plasticity rather than neuronal survival, this work offers a unique opportunity to study differential functions of BDNF in the brain.

    View all comments by Bai Lu
  4. Yano and colleagues managed to proceed one step further in elucidating synaptic actions of neurotrophins. Although it was well established for quite some time that BDNF exerts presynaptic effects on the availability of presynaptic glutamate vesicles for synaptic transmission, the molecular determinants of this action were far from being understood. This paper now highlights new downstream signaling partners in the presynaptic actions of BDNF.

    The observation, in the early 1990s, that BDNF can enhance presynaptic functions of excitatory synapses (Lohof et al., 1993; Lessmann et al., 1994) was followed shortly thereafter by the discovery of an essential role of BDNF in Schaffer collateral LTP (Korte et al., 1995; Patterson et al., 1996). Also, in 1996, Figurov and colleagues (1996) found that one of the important presynaptic actions of BDNF is to avoid transmitter vesicle depletion upon repetitive activity of juvenile synapses, although this presynaptic BDNF effect cannot account for the impaired LTP in adult animals. It took another four years to learn, from the data by Jovanovic et al. (2000), that the effect of BDNF on availability of glutamate vesicles is mediated via synapsin 1, which is kind of a “chassis” for the transport of glutamate vesicles along actin filaments, to facilitate their “in time” arrival at the presynaptic active zone.

    With their most recent paper, Yano and coworkers now provide evidence that the actin-dependent motor protein Myo6 is linked via the adapter protein GIPC-1 to the transport of glutamate vesicles into the terminal. Important as this finding is, it raises—as new data usually do—a number of new issues concerning the molecular players involved in the presynaptic actions of BDNF, such as the following:

    1. What is the molecular impact of BDNF/TrkB signaling on the functions of GIPC-1 and Myo6, and is there a direct link to synapsin 1 function in vesicle transport?

    2. Since the basal presynaptic phenotype of the Myo6-/- and the GIPC-1-/- mice seems to be rather robust, acute knockdown of these proteins via siRNA in normally developed hippocampal neurons would further strengthen a direct and specific functional link of these proteins to the presynaptic modulation by BDNF.

    3. Given the also very prominent postsynaptic expression of Myo6 and GIPC-1 (and TrkB can be postsynaptic, too), the routes of postsynaptic actions of these downstream signaling molecules would be exciting to investigate. This is especially true, given that CA1-LTP is prominently expressed at postsynaptic locations (Malinow, 2003) and that Myo6 is involved in postsynaptic AMPA receptor shuttling, which mediates this form of LTP.

    4. The absence of any effects of Myo6 or GIPC knockouts, respectively, on LTP in adult animals raises questions about whether the LTP protocol was sensitive for pre- and postsynaptic BDNF signaling, or whether compensatory mechanisms were at work in these animals and might be responsible for bypassing BDNF signaling in postsynaptic LTP in these animals in adulthood.

    5. Finally, given the modulation of dopamine release via BDNF signaling (Blochl et al., 1996), it is tempting to speculate that BDNF, via the Myo6-GIPC-1 signaling, could also participate in the pathophysiology of Huntington and Parkinson diseases, known to originate from low dopamine release in the striatum. And even more exciting, Myo6 and GIPC could also participate in the trafficking of BDNF vesicles, which are known to depend on kinesin- and especially dynein-dependent motors in axons and dendrites (Gauthier et al., 2004).

    Of course, asking all these questions is much easier than finding the answers, and it is inherent to the paper by the Chao lab that we are now able to ask even more precise new questions regarding these topics.

    View all comments by Volkmar Lessmann

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  1. Trisomy Trouble: Neurotrophin Signaling Defective in Down Syndrome