Soluble Amyloid-β42 Stimulates Glutamate Release through Activation of the α7 Nicotinic Acetylcholine Receptor

Abstract

Abstract. Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss and hippocampal atrophy. Soluble amyloid-␤ (A␤) 42 and plaque accumulation is implicated as the neurotoxic species in this disorder; however, at physiological concentrations (pM-nM), A␤ 42 contributes to neurogenesis, long-term potentiation, and neuromodulation. Because A␤ 42 binds the ␣7 nicotinic acetylcholine receptors (␣7nAChRs) located presynaptically on glutamatergic terminals, involved with hippocampal dependent learning and memory, we examined the effects of the human, monomeric isoform of A␤ 42 on glutamate release in the dentate gyrus (DG), CA3, and CA1, of isoflurane anesthetized, 6-9 month old male C57BL/6J mice. We utilized an enzyme-based microelectrode array selective for L-glutamate measures with fast temporal (4 Hz), low spatial resolution (50 × 100 m) and minimal damage to the surrounding parenchyma (50-100 m). Local application of A␤ 42 (0.01, 0.1, 1.0, and 10.0 M; ∼150 nl; 1-2 Seconds) elicited robust, reproducible glutamate signals in all hippocampal subfields studied. Local application of 0.1 and 1.0 M A␤ 42 significantly increased the average maximal amplitude of glutamate release compared to saline in the DG and CA1. 10.0 M A␤ 42 significantly elevated glutamate release in the DG and CA3, but not in the CA1. Glutamate release was completely attenuated with coapplication of 10.0 M ␣-Bungarotoxin, the potent ␣7nAChR antagonist. Coapplication of 10.0 M tetrodotoxin, indicates A␤ 42-induced glutamate release originates from neuronal rather than glial sources. This study demonstrates that the human, monomeric A␤ 42 isoform evokes glutamate release through the ␣7nAChR and varies across hippocampal subfields.

Identification of a common immune regulatory pathway induced by small heat shock proteins, amyloid fibrils, and nicotine

“…For samples treated with biotinylated Tau 623-628, six of the seven proteins were observed, with the GTP-binding protein RAN substituted for the RAS GTP-like activating protein (SI Appendix, Table S1). The results were consistent with the literature, which previously established that amyloid β binds NAChR (10,11,(18)(19)(20) and associates with NMDA glutamate receptor (21). KidIns220 is a scaffolding protein with multiple ankyrin repeats binding the A and B subunits of NMDA in neuronal tissue (22) but is not documented to bind the D subunit of the NMDA receptor, which is principally expressed in nonneuronal tissue (23).…”

Basal Forebrain Cholinergic Circuits and Signaling in Cognition and Cognitive Decline

“…Third is the potential role of presynaptic α7* AChRs as sites for Abeta peptide binding and activation of increased glutamate release in circuits related to cognition (Hascup and Hascup, 2016; Koukouli and Maskos, 2015; Lilja et al, 2011). It should also be noted that until recently, Abeta was thought to only interact with α7 homo-pentameric nAChRs.…”

“…Additional studies demonstrate that Abeta oligomers are ligands for nAChRs, and in the case of α7*nAChRs, low concentrations of Abeta (in the pM range) serve as agonist, whereas in the nM range Abeta is an antagonist (Puzzo et al, 2008). A recent report suggests that Abeta induced neuronal glutamate release in the hippocampus by activating α7* nAChRs (Hascup and Hascup, 2016). In primary cortical neuronal cultures, activation of α4 β2* nAChR protects against Aβ peptide induced cytotoxicity (Kihara et al, 1998), and in hippocampal slice recordings, an α4β2*nAChR selective agonist reversed Abeta impairment of LTP induction (Wu et al, 2008).…”

“…Cellular mechanisms of cholinergic neuronal loss and subsequent disruption of target hippocampal & cortical domains. Possible mechanisms thought to underlie early loss of cholinergic projections in an animal model of AD-like dementia: Aβ induced excitotoxicity mediated by interaction with α7* nAChRs (Hascup & Hascup, 2016; Liu et al, 2016; Wu et al, 2016), and impaired neurotrophin–induced retrograde transport via Rab5 endosome enlargement (Xu et al, 2015). Images for A adapted from human brain atlas (Hawrylycz et al, 2012)…”

Amyloid-β Impairs Vesicular Secretion in Neuronal and Astrocyte Peptidergic Transmission

“…Binding of Aβ to neuronal and glial plasma membranes causes multiple aberrant effects that could trigger synaptic failure, such as dysfunction of Ca 2+ homeostasis, axonal transport, neurotransmitter receptors and transporters and mitochondria. Moreover, several studies have proposed that Aβ peptides can affect synaptic function by altering vesicular release of classical transmitters (i.e., glutamate) from neurons and astrocytes (Arias et al, 1995; Abramov et al, 2009; Parodi et al, 2010; Brito-Moreira et al, 2011; Talantova et al, 2013; Hascup and Hascup, 2016). In this regard, two recent studies showing that Aβ oligomers directly impair SNARE complex formation and synaptic vesicle (SV) exocytosis further support a deleterious function of aberrant Aβ on transmitter secretion (Russell et al, 2012; Yang et al, 2015).…”