Paper
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Lawrence JL, Tong M, Alfulaij N, Sherrin T, Contarino M, White MM, Bellinger FP, Todorovic C, Nichols RA. Regulation of presynaptic Ca2+, synaptic plasticity and contextual fear conditioning by a N-terminal β-amyloid fragment. J Neurosci. 2014 Oct 22;34(43):14210-8. PubMed.
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From when we first discovered that the β/α generated fragment Aβ1-15 increased in response to γ-secretase inhibitor (GSI) treatment, we have wondered whether inducing the α-secretase pathway is “good or bad.” Lawrence and colleges clearly show that inducing this pathway is good, and their speculation on optimizing the production of Aβ1-15 is intriguing. With the knowledge that several GSIs have failed in clinical trials, some due to worsening in cognition, it is important to follow up the data presented and investigate how it translates into humans.
Washington University
This study by Lawrence et al. on the activity of the N-terminal fragment of Aβ raises some important questions regarding the physiological roles of APP cleavage products. As APP is cleaved, it makes sense that the products could serve as activity-dependent feedback with downstream effects that regulate the system. Whether this feedback is functioning properly (physiologically normal) or impaired (pathological) could influence disease conditions. There are well-documented cases of redundancy in many systems, and the set of experiments identifying the two histidines (his-13 and his-14) and the YEVHHQ region as the key component of the functional effects of the N-terminal domain of Aβ are particularly compelling. Although there are many more combinations of Aβ fragments to examine in this way, this is an important mechanistic finding.
These results also raise many questions about modulatory effects of the full-length Aβ peptide and specific cleavage products that will be important to study in further depth. Is the improved conditioned fear performance seen on administration of low concentration of Aβ42 due to processing of the peptide to Aβ1-15? (Could Aβ1-15 be measured in tissue to see if Aβ1-42 is cleaved after injection?) Or, could the neuromodulatory activity of Aβ1-15 be retained in the full-length peptide under specific conformations (i.e., is the 1-15 region within Aβ1-42 accessible)? Do the positive effects seen on pretreatment with Aβ1-15 represent competition of the peptide with Aβ1-42, rather than Aβ1-15 signaling through a receptor that protects the system? Would the same effects be seen by pretreating with an α7-nicotinic agonist?
The initial reports that low concentrations of Aβ could augment synaptic signaling seemed contrary to a large literature that high concentrations of Aβ potently inhibit synaptic plasticity. However, several independent groups, including nice studies by Dr. Nichols’ group, have now shown picomolar concentrations of Aβ do, in fact, augment synaptic plasticity and behavior. That low and high concentrations of Aβ (or its fragments) can have opposing effects has been underappreciated. Moving forward, it will be important to keep in mind the effect of a very wide range of Aβ concentrations on plasticity, as well as have a renewed interest in all APP fragments.
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