. Amyloid-beta as a positive endogenous regulator of release probability at hippocampal synapses. Nat Neurosci. 2009 Dec;12(12):1567-76. PubMed.

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  1. This is quite an interesting paper. Abramov and colleagues carefully investigated the role of Aβ in presynaptic function, and found that Aβ works as a positive regulator of transmitter release. This is the first report on a physiological role of Aβ as far as I know. Because increased Aβ enhances basal transmitter release, GABA signals may be increased in APP Tg mice to keep a balance between excitation and inhibition of neurons as Mucke reported (see Palop et al., 2007).

    In their figure 7d, Abramov and colleagues showed that presynaptic facilitation by bursts was diminished by both increased and reduced levels of Aβ. Thus, an appropriate level of Aβ may be required for maintaining healthy synaptic activity. This result may explain why Aβ immunization does not clearly halt a progression of dementia.

    I would like to hear Dr. Mucke's opinion.

    References:

    . Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. Neuron. 2007 Sep 6;55(5):697-711. PubMed.

  2. Taken together, the findings of this intriguing study suggest a novel role for endogenous Aβ as a positive modulator of excitatory transmission. Acutely increasing levels of Aβ rapidly and reversibly increased the number of active synapses and the amount of neurotransmitter released by each active synapse. Acutely reducing levels of Aβ reduced the number of active synapses by about half, with more modest effects on neurotransmitter release. While the data presented are compelling, they are hard to reconcile with previous reports that have suggested an inhibitory role for Aβ. In particular, they would seem to conflict with the lack of effect of acute inhibition of Aβ production on basal transmission in hippocampal slices (Kamenetz et al., 2003). One can, however, imagine scenarios where small differences in the concentration of Aβ, oligomeric state of the peptide, and/or the duration of synaptic exposure, could shift the balance between positive and negative feedback regulation. Indeed, Abramov et al. report that longer-term (48 hours) inhibition of Aβ degradation decreased the number of active synapses. Future experiments will be needed to tease apart the specific roles of endogenous Aβ under a variety of normal conditions and at different stages of Alzheimer disease.

    References:

    . APP processing and synaptic function. Neuron. 2003 Mar 27;37(6):925-37. PubMed.

    View all comments by Jane Sullivan
  3. This is a detailed and elegant study reporting on acute changes in pre-synaptic release probability related to β amyloid (although it seems that the authors cannot fully rule out a role also of βC-terminal fragments of APP). Intriguingly, they provide evidence that Aβ plays a role in history-dependent enhancement of synaptic transmission. This paper builds on other recent studies providing evidence for a physiological role of Aβ at synapses. This group has a lot of expertise in these methods, and it is exciting to get such an excellent new group into the field of AD research. At the same time, one can speculate that if another group with expertise in post-synaptic mechanisms did a similarly detailed study, they might find some direct effects there as well.

    It is difficult to isolate pre- and post-synapses since, of course, they relate to each other. APP certainly traffics to both ends of the neuron and Aβ also localizes to both ends. What APP and Aβ are doing at synapses remains unclear, although this study provides new insights on acute pre-synaptic effects. They interpret that extracellular Aβ is the driving force behind the synaptic enhancement that they observed, although in their only experiments directly applying extracellular Aβ (Supplementary Fig. 5), they apparently required several orders of magnitude higher levels of the peptide than they find released endogenously. Our recent study showed that neprilysin also regulates the intraneuronal pool of Aβ (Tampellini et al., 2009).

    At the end of their discussion, the authors then turn to how their work might relate to AD. Specifically, they look at the potential deleterious effect of having too much Aβ in the setting of more prolonged (48 hours) inhibition of neprilysin. Interestingly, and in agreement with our previous publication on transgenic compared to wild-type neurons (Almeida et al., 2005), they observed (in Supplementary Fig. 10) reduced but enlarged FM1-43 puncta/pre-synapses.

    References:

    . Synaptic activity reduces intraneuronal Abeta, promotes APP transport to synapses, and protects against Abeta-related synaptic alterations. J Neurosci. 2009 Aug 5;29(31):9704-13. PubMed.

    . Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses. Neurobiol Dis. 2005 Nov;20(2):187-98. PubMed.

    View all comments by Gunnar Gouras