The Neuroprotection of Liraglutide on Alzheimer-Like Learning and Memory Impairment by Modulating the Hyperphosphorylation of Tau and Neurofilament Proteins and Insulin Signaling Pathways in Mice

Abstract

The aim of this study was to investigate the effect of liraglutide on Alzheimer-like learning and memory impairment in mice, which were intracerebroventricularly (i.c.v.) injected with streptozotocin (STZ). Twenty-four mice were randomly divided into three groups: control (CON), AD model (STZ), and liraglutide-treated (LIR). The results show that both hyperphosphorylated tau and neurofilament proteins had deceased protein glycosylation and the tau bound to microtubules was lower in the STZ group compared to the CON group. The expression of JNK phosphorylation was higher and the number of Fluoro-Jade-B-positive degenerative neurons was increased in the STZ group as compared to both the CON and liraglutide groups. Escape latency in the STZ group was longer than that in both the CON and LIR groups, while the number of hidden platform crossings in path length was less than that in the other two groups. Liraglutide decreased the hyperphosphorylation levels of tau and neurofilament proteins, increased protein O-glycosylation, increased tau bound to microtubules, and also significantly improved the learning and memory ability of the mice. These results suggest that the effects of liraglutide on decreasing the hyperphosphorylation of tau and neurofilament proteins by enhancing O-glycosylation of neuronal cytoskeleton protein, improving the JNK and ERK signaling pathway, and reducing neural degeneration may be related to its protective effects on AD-like learning and memory impairment induced by i.c.v. injection of STZ. Our results indicate that GLP-1 analogs represent a novel treatment strategy for Alzheimer's disease.

Common defects of mitochondria and iron in neurodegeneration and diabetes (MIND): A paradigm worth exploring

“…Results regarding the potential of an FDA approved treatment for T2D in a transgenic FAD mouse model were released in September of 2013. Liraglutide, a glucagon mimetic and GLP-1 agonist used to stimulate insulin secretion in the presence of glucose, was shown to result in decreased tau phosphorylation, decreased neurofilament formation, and increased memory performance and ability in mice [154]. This is consistent with previous findings that demonstrated reduced plaque formation and oxidative stress in transgenic mice treated with GLP-1 [155].…”

Incretin-based therapy for type 2 diabetes mellitus is promising for treating neurodegenerative diseases

“…Furthermore, in an AD rat model induced by the intrahippocampal injection of Aβ, liraglutide (Han et al, 2013) and Val(8)GLP-1 (Wang et al, 2010 activate cAMP signaling in the brain and protect rats against the Aβ-induced impairments of spatial memory and deficit of LTP in a dose-dependent manner. In the rodent model of sporadic AD by intracerebroventricular injection with streptozotocin (STZ), liraglutide (Xiong et al, 2013), (Chen et al, 2012), Val(8)GLP-1 (Li et al, 2012a), and geniposide (Gao et al, 2014) decrease the hyperphosphorylation of τ and neurofilament proteins. In the P301L mouse model of tauopathy, liraglutide furthermore reduced the levels of tangles and hyperphosphorylated τ (Hansen et al, 2015).…”

Incretin mimetics as pharmacologic tools to elucidate and as a new drug strategy to treat traumatic brain injury

“…(ii) Peripheral neuropathy: promoting neurite outgrowth and inhibiting neuron dysfunction and loss [117,141-144]. (iii) Stroke: reducing stroke volume and neuroinflammation, and augmenting neuronal survival and neurogenesis [118,145-149]. (iv) PD: augmenting dopaminergic cell survival, reducing neuroinflammation, increasing neurogenesis and improving motor coordination [118,150-152], which has recently translated to motor and cognitive improvements in moderately affected PD patients in an open label clinical trial [153].…”