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  • br Materials and methods br Contributors br Acknowledgements

    2021-10-11


    Materials and methods
    Contributors
    Acknowledgements This work was funded by the Ministry of Human Resources and Social Security, Shanxi Province [(2010)255], by a Shanxi Scholarship Council of China, and supported by a grant from the Alzheimer Society UK. The authors declare no conflict of interest
    Introduction Alzheimer’s disease (AD) is the most common neurodegenerative disorder and it is estimated that the population of dementia patient worldwide may reach 131.5 million in 2050 due to longer life-expectancy in the industrialized nations. The pathology of AD is characterized by the presence of neurofibrillary tangles composed of hyperphosphorylated tau protein (p-tau) and amyloid-β peptide accumulation, as well as neuronal loss in different Axitinib regions which are associated with progressive memory loss and cognitive decline [1], [2], [3]. Drug therapies for AD are currently restricted and mainly depend on three cholinesterase inhibitors and the receptor inhibitor memantine, but these drugs cannot fundamentally halt or delay the progression of the disease at present [4], [5], [6], [7]. Type 2 diabetes mellitus (T2DM) is a risk factor for developing AD [8], [9], [10]. Patients with T2DM present with learning and memory deficits [11] and there is an increase an approximately twofold risk of AD [8], [12]. Also, AD shares many pathophysiological features with T2DM, including insulin resistance, inflammatory stress and amyloid-β peptide accumulation [13]. Based on these shared features, insulin resistance is one of the key underlying mechanisms [12], [14], [15]. Incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) which can treat T2DM have been proposed as a novel therapeutic schedule for AD. Extensive preclinical studies show good effects in animal models of AD by reducing memory loss, synapse loss and amyloid plaque load [16], [17], [18], [19], decrease the hyperphosphorylation of τ protein [20], [21], [22], [23], exert anti-inflammatory function [24], [25], [26] and reduce neuronal loss [22], [27], [28]. A pilot study testing the GLP-1 analogue liraglutide in AD patients showed good protective effects in FDG-PET brain scans [29]. Other clinical trials in patients with AD or Parkinson’s disease (PD) are currently ongoing [30]. Dual GLP-1 and GIP receptor agonists have been developed to treat T2DM and have shown first positive results in patients with diabetes [31]. We have tested one of these dual agonists named DA-JC1 in the MPTP mouse model of PD with good results [32], [33]. Here, we are testing the newer dual agonist DA-JC4 that has been optimized to cross the blood-brain barrier in the icv. streptozotocin (STZ) rat model of AD. STZ desensitizes insulin signaling in the brain [34], [35] and produces a range of pathological changes that are also found in the brains of AD patients [13], [36], [37], such as inducing cognitive impairment [21], [38], [39], [40], chronic inflammation in the brain [41] and enhanced tau protein phosphorylation [22], [42].
    Materials and methods
    Results
    Discussion In the present study, we investigated the effect of the novel GLP-1/GIP dual receptor agonist DA-JC4 for the first time in the rat model of STZ- induced cognitive impairment. ICV. administration of STZ at low dosage (3 mg/kg body weight) induces learning and memory deficits [21], [38], [39], [40], [43]. Consistent with previous findings, we found that learning and memory impairment were induced by the STZ treatment. We also found that DA-JC4 effectively attenuated the spatial working memory deficit induced by STZ. Consistent with previous findings, the phosphorylation of tau protein was enhanced by icv. administration of STZ [42]. DA-JC4 treatment prevented or reversed the phosphorylation of tau. The chronic inflammation response in the brain is a critical element of AD progression [47], [48]. Chronic inflammation generates free radicals and increases the release of pro-inflammatory cytokines that are detrimental to neurons [49], [50]. Consistent with previous findings, the chronic inflammation response was clearly triggered by the treatment with STZ [41]. DA-JC4 effectively reduced the chronic inflammation response induced by STZ, and the ratio of BAX/Bcl-2 was much improved, demonstrating that cellular apoptotic signaling had been reduced by the novel drug. In addition, insulin signaling as shown in IRS-1 phosphorylation levels and Akt phosphorylation furthermore was re-sensitized by DA-JC4. Levels of pIRS-1 were reduced and of pAkt were enhanced to normalise second messenger cell signaling. The novel dual agonist showed good effects in improving these key biomarkers of neuropathological processes.