Amyloid-β depresses excitatory cholinergic synaptic transmission in Drosophila.
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.


CONCLUSIONS
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.
Department of Neurology, Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
Liqun
L
Fang
Jingjing
J
Duan
Dongzhi
D
Ran
Zihao
Z
Fan
Ying
Y
Yan
Naya
N
Huang
Huaiyu
H
Gu
Yulan
Y
Zhu
D016229:Amyloid beta-Peptides / Q000235:genetics / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified; D059329:Cholinergic Neurons / Q000502:physiology*; D004331:Drosophila melanogaster / Q000235:genetics; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics*; D006801:Humans; D008568:Memory / Q000502:physiology; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology*; D013569:Synapses / Q000235:genetics / Q000502:physiology*; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)