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  • br Results and Discussion br STAR Methods

    2022-05-11


    Results and Discussion
    STAR★Methods
    Author Contributions
    Conflicts of Interest J.P.F. is a consultant for AstraZeneca, BMS, Johnson and Johnson, Novo Nordisk, and Sanofi, a member of the advisory panel for AstraZeneca and Sanofi, a member of the speaker’s bureau for Sanofi and Novo Nordisk, and has received research support from AbbVie, AstraZeneca, Boehringer Ingelheim, BMS, Elcelyx, Eli Lilly & Co., Ionis, Janssen, Johnson and Johnson, Ligand, Merck, Mylan, Novartis, Novo Nordisk, Pfizer, Sanofi, Theracos, and vTv. E.J.B. was Vice President Medical for MB2 LLC; Principal, Diabetes Drug Development Associates LLC; Scientific Consultant to Viacyte, Inc.; and Associate Professor at Indiana University School of Medicine. L.V. was a consultant for MB2 LLC. M.H.T. is a consultant for Bionorica SE, an advisor for Novo Nordisk, and a member of the scientific advisory board of ERX Pharmaceuticals, Inc.; he also receives research funds from Novo Nordisk. C.S. is an employee of F. Hoffman-La Roche AG. K.O. and R.D.D. are employees and K.O. is shareholder of Novo Nordisk. R.H.C. was employed at Novo Nordisk during preparation of the article. Furthermore, R.D.D. is co-inventor of the peptide IP.
    Acknowledgments
    Introduction Alzheimer’s disease (AD), is a progressive neurodegenerative disease, characterized clinically by progressive memory loss, cognitive decline, and aberrant behavior [1]. Currently, there is no treatment can improve this condition. Epidemiological studies have shown that type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer disease (AD) (Luchsinger et al., 2004, Ohara et al., 2011). The underlying mechanism is most likely that insulin signaling is impaired in the brains of AD patients (Moloney et al., 2010, Talbot et al., 2012). This motivated research in drugs that have shown good effects in treating diabetes to investigate if they could be helpful in treating AD as well. Previous studies have shown that the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) can play a neuroprotective role in the PCP inhibitor and show very promising effects in animal models of AD (Duffy and Holscher, 2013, Faivre and Holscher, 2013b, Li et al., 2010, McClean et al., 2011, McClean and Holscher, 2014). Glucagon (Gcg) is a hormone and growth-factor, and the Gcg receptor is expressed in the brain (Hoosein and Gurd, 1984, Mayo et al., 2003). Activation of the receptor can activate neuronal activity and cellular Ca2+ signaling and may have neuroprotective properties (Ayush et al., 2015). Here we test the effects of a triple receptor agonist (TA), which activates GIP-1, GIP and glucagon receptors at the same time. This novel drug has been developed as a potential treatment for diabetes (Finan et al., 2015). No studies have been published that test the neuroprotective effects of this novel drug. We therefore tested this promising TA in the APPSWE/PS1dE9 mouse model of AD. This mouse model recapitulates some of the hallmarks of AD, such as memory loss, synaptic loss, reduction of synaptic plasticity, reduction of neurogenesis in the dentate gyrus, chronic inflammation in the brain, and formation of amyloid plaques in the brain (Duffy and Holscher, 2013, Goto et al., 2008, Hamilton et al., 2011, Hamilton and Holscher, 2012, McClean et al., 2011). We tested the effects of TA in this transgenic mouse model and evaluated the neuroprotective effects. We analyzed memory formation, hippocampal neurogenesis, the expression levels of Brain Derived Neurotrophic Factor (BDNF) (Blurton-Jones et al., 2009), mitochondrial apoptosis signaling proteins, neuroinflammation and oxidative stress levels.
    Results
    Discussion The results demonstrate for the first time that the novel GLP-1/GIP/Gcg receptor agonist has clear neuroprotective effects in the APP/PS1 mouse model of AD. Memory formation in the spatial water maze task was improved by the drug, and the amyloid plaque load in the cortex and hippocampus was reduced. This result confirms our previous findings that single GLP-1 or GIP analogues can protect from memory loss in this mouse model of AD (Faivre and Holscher, 2013a, Faivre and Holscher, 2013b, McClean et al., 2011, McClean and Holscher, 2014). The chronic inflammation response as seen in the activation of microglia and astrocytes is much reduced by the novel TA, similar to single GLP-1 or GIP receptor agonists (Duffy and Holscher, 2013, Ji et al., 2016a, McClean et al., 2011). Levels of the peroxidized lipid 4-HNE that also acts as a pro-apoptotic signal in mitochondria have been reduced by the TA. 4-HNE is one of the markers of membrane lipid peroxidation induced by cytotoxic radicals such as OH. 4-HNE has cytotoxic, mutagenic and genotoxic properties and 4-HNE is reported to stimulate apoptosis via caspase 3 activation and by inducing mitochondrial damage as shown in cytochrome c release (Ji et al., 2001). The levels of the mitochondrial apoptosis signal BAX (Kim et al., 2005) were also reduced. Importantly, the anti-apoptotic signaling molecule B-cell lymphoma 2 (Bcl-2) which is active in functioning mitochondria that have normal inner membrane voltage potentials (Kavitha et al., 2013) is upregulated by the TA, adding to the neuroprotective effect. The level of chronic oxidative stress as measure by the levels of the oxidized nucleotide 8-Hydroxiguanosine (8-OHdG) was also reduced by the drug. Neurogenesis in the dentate gyrus was normalized. Importantly, the levels of the key growth factor BDNF were normalized in the brain. BDNF has shown clear neuroprotective effects in a range of animal models of disease (Allen et al., 2013, Benedetti et al., 2014, Blurton-Jones et al., 2009, Nagahara et al., 2013). An important factor of BNDF activity is that it maintains synaptic activity and protects synapses from stressors (Kuipers and Bramham, 2006). The observation that the synaptic marker synaptophysin was expressed at normal levels after TA treatment also indicates that synaptic numbers and function was improved in the AD mouse. We have shown previously that GLP-1 and GIP analogues protect synapses from amyloid induced stress and keeps them functional (Faivre and Holscher, 2013b, Gault and Holscher, 2008a, Gault and Holscher, 2008b, McClean and Holscher, 2014).