Metformin Attenuates Aβ Pathology Mediated Through Levamisole Sensitive Nicotinic Acetylcholine Receptors in a C. elegans Model of Alzheimer’ s Disease Waqar Ahmad 1 & Paul R. Ebert 1 Received: 17 June 2016 /Accepted: 24 August 2016 # Springer Science+Business Media New York 2016 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 Aβ 42 . We found that Aβ expressed in muscle inhibited levamisole sensitive nicotin- ic acetylcholine receptors and that metformin delayed Aβ- linked paralysis and improved acetylcholine neurotransmission in these animals. Metformin also moderated the effect of neu- ronal expression of Aβ: decreasing hypersensitivity to seroto- nin, 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 met- abolic modulators may be effective against AD and that the worm model can be used to identify the specific interactions between Aβ and cellular proteins. Keywords Metformin . Alzheimer’ s disease . AICAR . Oligomerization . C. elegans 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 Introduction Alzheimer’ s disease (AD), a common form of dementia that is especially prevalent in old age, is characterized by loss of brain neurons and impaired memory. An important patholog- ical hallmark of AD is the formation of amyloid beta (Aβ) plaques that can be deposited either extracellularly or intra- neuronally and disrupt neuronal functions [1, 2]. While the main cause of AD is still unknown, AD is associated with resistance to insulin, indicating that re-sensitizing insulin re- ceptors may be a useful therapy [3, 4]. Insulin resistance leads to type 2 diabetes mellitus (T2DM), an important risk factor in AD development that is associated with impaired insulin sig- naling and glucose metabolism [5–7]. A growing body of experimental and clinical research provides evidence that both AD and T2DM share many pathophysiological symptoms, indicating that drugs used for T2DM treatment also may alle- viate AD symptoms [8–12]. Metformin is a hypoglycemic agent that is the primary drug therapy used to treat T2DM. Metformin alters cellular energy metabolism by reducing glucose production by the liver, as well as by increasing the uptake of glucose into cells. Although the exact mechanism of action of metformin is not understood, metformin increases the NADH/NAD+ ratio and Electronic supplementary material The online version of this article (doi:10.1007/s12035-016-0085-y) contains supplementary material, which is available to authorized users. * Paul R. Ebert p.ebert@uq.edu.au 1 School of Biological Sciences, The University of Queensland, Brisbane 4072, Australia Mol Neurobiol DOI 10.1007/s12035-016-0085-y