Regulation of Presynaptic Ca²⁺, Synaptic Plasticity and Contextual Fear Conditioning by a N-terminal β-Amyloid Fragment

Abstract

Soluble ␤-amyloid has been shown to regulate presynaptic Ca 2ϩ and synaptic plasticity. In particular, picomolar ␤-amyloid was found to have an agonist-like action on presynaptic nicotinic receptors and to augment long-term potentiation (LTP) in a manner dependent upon nicotinic receptors. Here, we report that a functional N-terminal domain exists within ␤-amyloid for its agonist-like activity. This sequence corresponds to a N-terminal fragment generated by the combined action of ␣-and ␤-secretases, and resident carboxypeptidase. The N-terminal ␤-amyloid fragment is present in the brains and CSF of healthy adults as well as in Alzheimer's patients. Unlike full-length ␤-amyloid, the N-terminal ␤-amyloid fragment is monomeric and nontoxic. In Ca 2ϩ imaging studies using a model reconstituted rodent neuroblastoma cell line and isolated mouse nerve terminals, the N-terminal ␤-amyloid fragment proved to be highly potent and more effective than full-length ␤-amyloid in its agonist-like action on nicotinic receptors. In addition, the N-terminal ␤-amyloid fragment augmented theta burst-induced post-tetanic potentiation and LTP in mouse hippocampal slices. The N-terminal fragment also rescued LTP inhibited by elevated levels of full-length ␤-amyloid. Contextual fear conditioning was also strongly augmented following bilateral injection of N-terminal ␤-amyloid fragment into the dorsal hippocampi of intact mice. The fragment-induced augmentation of fear conditioning was attenuated by coadministration of nicotinic antagonist. The activity of the N-terminal ␤-amyloid fragment appears to reside largely in a sequence surrounding a putative metal binding site, YEVHHQ. These findings suggest that the N-terminal ␤-amyloid fragment may serve as a potent and effective endogenous neuromodulator.

Novel Insights into the Physiological Function of the APP (Gene) Family and Its Proteolytic Fragments in Synaptic Plasticity

“…The APLP1 protein shows the highest presence at the cell surface among all APP protein family members (Kaden et al, 2009; Mayer et al, 2016). As indicated Figure 2B depicts the APP protein family function at the presynaptic site, where the Aß, Aß-15 and possibly the APPsα domain interfere with glutamate release by activating nAChRs and enhancing intracellular Ca 2+ levels (Puzzo et al, 2008; Wang Z. et al, 2012; Lawrence et al, 2014). It is further hypothesized that homodimerized APP acts as a G-Protein coupled receptor which is activated by Aß and might be involved in neurotransmitter release following enhanced Ca 2+ influx.…”

“…It functions via binding to presynaptic APP homodimers (Fogel et al, 2014) or by activating α7-nAChRs (Tong et al, 2011). The study by Lawrence et al (2014) highlighted that the N-terminal domain of Aß contains this agonist-like activity of the Aß peptide. It was further suggested that successive α- and ß-secretase activity will release the short functional domain, named Aß1–15 (or Aß1–16, Portelius et al, 2011).…”

“…It was further suggested that successive α- and ß-secretase activity will release the short functional domain, named Aß1–15 (or Aß1–16, Portelius et al, 2011). With regard to synaptic plasticity, Aß1–15 significantly enhances PTP and LTP without altering baseline synaptic transmission at femtomolar concentrations, while higher amounts had no effect on hippocampal LTP (Lawrence et al, 2014). During LTD, Aß was shown to have a facilitating role through mGluR and NMDA-R due to the altered glutamate recycling at synapses (Li et al, 2009; Chen et al, 2013).…”

The keystone of Alzheimer pathogenesis might be sought in Aβ physiology

“…The mechanisms underlying the physiological role of Aβ involved K + and Ca 2+ ion channels and several key receptors for synaptic function such as glutamatergic and cholinergic receptors. In particular, we have focused on nAchRs because i) they play a fundamental role in learning and memory in physiological conditions (Levin, 2002; Albuquerque et al, 2009; Yakel et al, 2013; 2014); ii) the cholinergic deficit is closely related to the pathogenesis of AD (Levey, 1996; Clader and Wang, 2005; Oddo and La Ferla, 2006; Yakel, 2013); iii) Aβ has a picomolar affinity for α7-nAChRs (Wang et al, 2000); iv) Aβ modulate α7-nAChR function (Dougherty et al, 2003; Small et al, 2007; Khan et al, 2010; Lawrence et al, 2014) and it is able to act as an agonist or an antagonist depending upon the dose, as previously discussed (Dineley et al, 2002; Grassi et al, 2003; Fodero et al, 2004). [Please see Dineley, 2007 for a review on Aβ-nAChR interaction in health and disease].…”

“…In our works (Puzzo et al, 2008; 2011) we have shown that a pharmacological or genetic blockage of α7-nAChRs resulted in inhibition of the Aβ-induced increase of post-tetanic potentiation, LTP and memory; moreover the inhibition of endogenous Aβ did not affect synaptic plasticity in α7-nAChR-KO, supporting the hypothesis that the physiological effect of low Aβ concentrations is mediated by α7-nAChRs. A recent paper (Lawrence et al, 2014) has shown that an Aβ N-terminal fragment exerts a highly potent agonist-like action on nicotinic receptors, boosting LTP and contextual fear memory that, in turn, was attenuated by co-administration of a nicotinic antagonist.…”