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Amyloid-β depresses excitatory cholinergic synaptic transmission in Drosophila.

ABSTRACT: 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.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.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.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.

SUBMITTER: Fang L

PROVIDER: S-EPMC5561919 | biostudies-other | 2012 Oct

REPOSITORIES: biostudies-other

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Project description:Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels. The α7 subtype of nAChRs is involved in neurological pathologies such as Parkinson's disease, Alzheimer's disease, addiction, epilepsy and autism spectrum disorders. The Drosophila melanogaster α7 (Dα7) has the closest sequence homology to the vertebrate α7 subunit and it can form homopentameric receptors just as the vertebrate counterpart. The Dα7 subunits are essential for the function of the Giant Fiber circuit, which mediates the escape response of the fly. To further characterize the receptor function, we generated different missense mutations in the Dα7 nAChR's ligand binding domain. We characterized the effects of targeted expression of two UAS-constructs carrying a single mutation, D197A and Y195T, as well as a UAS-construct carrying a triple D77T, L117Q, I196P mutation in a Dα7 null mutant and in a wild type background. Expression of the triple mutation was able to restore the function of the circuit in Dα7 null mutants and had no disruptive effects when expressed in wild type. In contrast, both single mutations severely disrupted the synaptic transmission of Dα7-dependent but not glutamatergic or gap junction dependent synapses in wild type background, and did not or only partially rescued the synaptic defects of the null mutant. These observations are consistent with the formation of hybrid receptors, consisting of D197A or Y195T subunits and wild type Dα7 subunits, in which the binding of acetylcholine or acetylcholine-induced conformational changes of the Dα7 receptor are altered and causes inhibition of cholinergic responses. Thus targeted expression of D197A or Y195T can be used to selectively disrupt synaptic transmission of Dα7-dependent synapses in neuronal circuits. Hence, these constructs can be used as tools to study learning and memory or addiction associated behaviors by allowing the manipulation of neuronal processing in the circuits without affecting other cellular signaling.

Project description:BackgroundAlzheimer's disease (AD) is the most common form of age-related neurodegenerative diseases. Cerebral deposition of Aβ peptides, especially Aβ42, is considered the major neuropathological hallmark of AD and the putative cause of AD-related neurotoxicity. Aβ peptides are produced by sequential proteolytic processing of APP, with β-secretase (BACE) being the initiating enzyme. Therefore, BACE has been considered an attractive therapeutic target in AD research and several BACE inhibitors have been tested in clinical trials, but so far, all have had negative outcomes or even led to worsening of cognitive function. AD can be triggered by Aβ years before the first symptoms appear and one reason for the failures could be that the clinical trials were initiated too late in the disease process. Another possible explanation could be that BACE inhibition alters physiological APP processing in a manner that impairs synaptic function, causing cognitive deterioration.MethodsThe aim of this study was to investigate if partial BACE inhibition, mimicking the putative protective effect of the Icelandic mutation in the APP gene, could reduce Aβ generation without affecting synaptic transmission. To investigate this, we used an optical electrophysiology platform, in which effects of compounds on synaptic transmission in cultured neurons can be monitored. We employed this method on primary cortical rat neuronal cultures treated with three different BACE inhibitors (BACE inhibitor IV, LY2886721, and lanabecestat) and monitored Aβ secretion into the cell media.ResultsWe found that all three BACE inhibitors tested decreased synaptic transmission at concentrations leading to significantly reduced Aβ secretion. However, low-dose BACE inhibition, resulting in less than a 50% decrease in Aβ secretion, did not affect synaptic transmission for any of the inhibitors tested.ConclusionOur results indicate that Aβ production can be reduced by up to 50%, a level of reduction of relevance to the protective effect of the Icelandic mutation, without causing synaptic dysfunction. We therefore suggest that future clinical trials aimed at prevention of Aβ build-up in the brain should aim for a moderate CNS exposure of BACE inhibitors to avoid side effects on synaptic function.

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Amyloid-β depresses excitatory cholinergic synaptic transmission in Drosophila.

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