Amyloid-β depresses excitatory cholinergic synaptic transmission in Drosophila

Abstract

Objective Decline, disruption, or alterations of nicotinic cholinergic mechanisms contribute to cognitive dysfunctions like Alzheimer's disease (AD). Although amyloid-β (Aβ) aggregation is a pathological hallmark of AD, the mechanisms by which Aβ peptides modulate cholinergic synaptic transmission and memory loss remain obscure. This study was aimed to investigate the potential synaptic modulation by Aβ of the cholinergic synapses between olfactory receptor neurons and projection neurons (PNs) in the olfactory lobe of the fruit fly. Methods Cholinergic spontaneous and miniature excitatory postsynaptic current (mEPSC) were recorded with whole-cell patch clamp from PNs in Drosophila AD models expressing Aβ40, Aβ42, or Aβ42Arc peptides in neural tissue. Results In fly pupae (2 days before eclosion), overexpression of Aβ42 or Aβ42Arc, but not Aβ40, led to a significant decrease of mEPSC frequency, while overexpression of Aβ40, Aβ42, or Aβ42Arc had no significant effect on mEPSC amplitude. In contrast, Pavlovian olfactory associative learning and lifespan assays showed that both short-term memory and lifespan were decreased in the Drosophila models expressing Aβ40, Aβ42, or Aβ42Arc. Conclusion Both electrophysiological and behavioral results showed an effect of Aβ peptide on cholinergic synaptic transmission and suggest a possible mechanism by which Aβ peptides cause cholinergic neuron degeneration and the consequent memory loss.

Modeling the complex pathology of Alzheimer's disease in Drosophila

“…These critical changes in the presynaptic terminal preceded and might be responsible for the loss of presynaptic boutons. Similar reduction in synaptic activity was confirmed in cholinergic projection neurons of the olfactory system in pupae, which resulted in altered short-term memory (Fang et al, 2012), a significant finding because AD affects mainly cholinergic systems in the human brain. A study to pinpoint the mechanisms by which Aβ42 mediates memory loss found that Aβ42 stimulated PI3K-Akt signaling , which causes reduced long-term potentiation (LTP) (Fig.…”

Gender-Specific Hippocampal Dysrhythmia and Aberrant Hippocampal and Cortical Excitability in the APPswePS1dE9 Model of Alzheimer’s Disease

“…This paradoxical situation might be explainable given the sophisticated pathophysiology of the septohippocampal system and the heterogeneity, that is, dualistic theory of hippocampal theta activity, that is, hippocampal theta being differentiated into atropine-insensitive type I and atropine-sensitive type II theta [40, 60]. It has been reported that A β can modulate cholinergic and glutamatergic neurons in the septohippocampal system [61–64] and that the presence of A β in both the medial septum and the hippocampus can dampen theta rhythm in vitro and in vivo [62, 65–69] which is associated with cognitive impairment.…”

Role of Drosophila Amyloid Precursor Protein in Memory Formation

“…Thus, similarities between Aβ-induced neurotoxic biochemical pathways in flies and humans make Drosophila a relevant model to study the molecular basis of AD pathogenesis. Neuronal expression of human Aβ42 leads to a learning deficit in young flies, and MTM deficit in older flies (Iijima et al, 2004, 2008; Fang et al, 2012). Likewise, neuronal overexpression of hAPP alters learning and MTM in young flies and these deficits become more pronounced as the fly ages (Sarantseva et al, 2009).…”