. Amyloid Beta Peptides Block New Synapse Assembly by Nogo Receptor-Mediated Inhibition of T-Type Calcium Channels. Neuron. 2017 Oct 11;96(2):355-372.e6. PubMed.


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  1. Zhao et al. present an interesting study with a clearly presented mechanism proposing how exogenously applied ADDLs can result in synaptic decline via a reduction in Nogo-regulated spine assembly. This involves an inhibition of the low threshold, low conductance, transiently activated T-type voltage-gated calcium channel (VGCC) found in the dendrites and soma of a wide array of neurons throughout the brain. In broad terms, the focus on mechanisms of synaptic loss is strategic and exciting, and the senior author is well-versed in Nogo signaling and synapse formation. In comparison, it was unclear if there was a comparable command of the complexities of AD with regard to calcium signaling and synaptic physiology, as multiple synaptic and calcium signaling cascades that contribute to synaptic decline were omitted from consideration or discussion. The list can be rather long but includes SOCC, ER, lysosomal and mitochondrial stores, MCU, ion exchangers, etc. This was further complicated by questionable assumptions about synaptic plasticity deficits in AD models; for example, the authors presumed postsynaptic causation based on the lack of differences in the paired-pulse ratio (PPR); however, profound and early presynaptic deficits exist, including in PPR, as we and others have demonstrated across many models (e.g., Chakroborty et al., 2009; Chakroborty et al., 2012; de Wilde et al., 2016).When considering the properties of the T-type channel, which can generate inward calcium currents at rest and is highly expressed in the thalamus and other relatively resilient regions, the lack of correlation between its distribution and AD pathology is curious. Clearly, the dynamics are complex, and worthy of additional study.

    The focus on using synthetic ADDLs specifically is an additional source of interest, and one wonders what effects different or endogenous mixtures of amyloid peptide species would exert on this proposed mechanism. While there is little doubt that certain Aβ species disrupt calcium signaling, the mechanisms and conditions are unclear. For example, there is little effect of amyloid plaques on activity-dependent calcium signaling in confirmed hippocampal neurons (Briggs et al., 2013), yet multiple studies demonstrate oligomers can create Ca2+ permeable pores in membranes (e.g., Demuro et al., 2005; Ullah et al., 2015). 

    Investigating if and how Aβ peptides increase synapse elimination or reduce synapse formation is valid and motivating for the field, and studies such as Zhao et al. can provide an essential and needed framework. These and related future questions would be of enhanced interest if probed in mature neurons or in vivo, as the perinatal and developmentally young neurons harvested for much of these studies express a distinct population of channels and signaling systems uniquely designed for structural plasticity, harboring the ability to extend, retract, and respond to cues that aren’t fully replicated in adult, or even aged, neuronal populations. It is not yet clear from this study how much of the developmental machinery present only in the perinatal stages contribute to some of the mechanisms proposed for synapse loss in AD.  


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  1. For Synapses, Are Aβ Oligomers a No-Go?