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Metformin Attenuates Aβ Pathology Mediated Through Levamisole Sensitive Nicotinic Acetylcholine Receptors in a C. elegans Model of Alzheimer’s Disease

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Abstract

The metabolic disease, type 2 diabetes mellitus (T2DM), is a major risk factor for Alzheimer’s disease (AD). This suggests that drugs such as metformin that are used to treat T2DM may also be therapeutic toward AD and indicates an interaction between AD and energy metabolism. In this study, we have investigated the effects of metformin and another T2DM drug, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) in C. elegans expressing human Aβ42. We found that Aβ expressed in muscle inhibited levamisole sensitive nicotinic acetylcholine receptors and that metformin delayed Aβ-linked paralysis and improved acetylcholine neurotransmission in these animals. Metformin also moderated the effect of neuronal expression of Aβ: decreasing hypersensitivity to serotonin, restoring normal chemotaxis, and improving fecundity. Metformin was unable to overcome the small effect of neuronal Aβ on egg viability. The protective effects of metformin were associated with a decrease in the amount of toxic, oligomeric Aβ. AICAR has a similar protective effect against Aβ toxicity. This work supports the notion that anti-diabetes drugs and metabolic modulators may be effective against AD and that the worm model can be used to identify the specific interactions between Aβ and cellular proteins.

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Abbreviations

AD:

Alzheimer’s disease

AICAR:

5-Aminoimidazole-4-carboxamide ribonucleotide

AMP:

Adenosine monophosphate

AMPK:

5′ AMP-activated protein kinase

Aβ:

Amyloid beta

BACE1:

Beta-secretase 1

CI:

Chemotaxis index

T2DM:

Type 2 diabetes mellitus

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Acknowledgments

We thank Jürgen Goetz for providing valuable suggestions and guidance related to AD, as well as Mazhar Hussain and Sultan Asad for assisting with protein immunoblotting. The C. elegans strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). WA was supported by an IPRS PhD scholarship from the Australian government as well as UQCent scholarship from the University of Queensland.

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    Waqar Ahmad & Paul R. Ebert

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Correspondence to Paul R. Ebert.

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Ahmad, W., Ebert, P.R. Metformin Attenuates Aβ Pathology Mediated Through Levamisole Sensitive Nicotinic Acetylcholine Receptors in a C. elegans Model of Alzheimer’s Disease. Mol Neurobiol 54, 5427–5439 (2017). https://doi.org/10.1007/s12035-016-0085-y

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  • DOI: https://doi.org/10.1007/s12035-016-0085-y

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