Peripheral and Central Effects of Memantine in a Mixed Preclinical Mice Model of Obesity and Familial Alzheimer’s Disease

Abstract

There is growing evidence that obesity associated with type 2 diabetes mellitus (T2DM) and aging are risk factors for the development of Alzheimer's disease (AD). However, the molecular mechanisms through which obesity interacts with β-amyloid (Aβ) to promote cognitive decline remains poorly understood. Memantine (MEM), a N-methyl-D-aspartate receptor antagonist, is currently used for the treatment of AD. Nonetheless, few studies have reported its effects on genetic preclinical models of this neurodegenerative disease exacerbated with high-fat diet (HFD)-induced obesity. Therefore, the present research aims to elucidate the effects of MEM on familial AD HFD-induced insulin resistance and learning and memory impairment. Furthermore, it aspires to determine the possible underlying mechanisms that connect AD to T2DM. Wild type and APPswe/PS1dE9 mice were used in this study. The animals were fed with either chow or HFD until 6 months of age, and they were treated with MEM-supplemented water (30 mg/kg) during the last 12 weeks. Our study demonstrates that MEM improves the metabolic consequences produced by HFD in this model of familial AD. Behavioural assessments confirmed that the treatment also improves animals learning abilities and decreases memory loss. Moreover, MEM treatment improves brain insulin signalling upregulating AKT, as well as cyclic adenosine monophosphate response element binding (CREB) expression, and modulates the amyloidogenic pathway, which, in turn, reduced the accumulation of Aβ. Moreover, this drug increases the activation of molecules involved with insulin signalling in the liver, such as insulin receptor substrate 2 (IRS2), which is a key protein regulating hepatic resistance to insulin. These results provide new insight into the role of MEM not only in the occurrence of AD treatment, but also in its potential application on peripheral metabolic disorders where Aβ plays a key role, as is the case of T2DM.

The Involvement of Peripheral and Brain Insulin Resistance in Late Onset Alzheimer’s Dementia

“…Besides, they reported that Memantine—a drug which is currently used in AD treatment- showed an ameliorating effect on T2DM. This is in accordance with results published by our research group and others, where the benefits of Memantine administration were demonstrated in a mixed murine model of T2DM and AD (Sato and Morishita, 2013; Shinohara and Sato, 2017; Ettcheto et al, 2018b; Deng et al, 2019).…”

Aging Reduces Estradiol Protection Against Neural but Not Metabolic Effects of Obesity in Female 3xTg-AD Mice

“…Indeed, metabolic dysfunction has been widely hypothesized to be a key mechanism by which obesity induces neural deficits and increases AD risk (O'Brien et al, 2017;Pugazhenthi et al, 2017;Alford et al, 2018). Consistent with this position, previous work has shown interventions that reduce obesity in transgenic mouse models of AD also improve behavioral and pathological outcomes (Maesako et al, 2012;Walker et al, 2017;Yeh et al, 2017;Ettcheto et al, 2018). However, the current findings are not supportive of direct associations between improved metabolic profile and reduced AD-related indices.…”

Diet‐induced insulin resistance elevates hippocampal glutamate as well asVGLUT1 andGFAPexpression in AβPP/PS1 mice

“…As such, this mechanism helps to explain the cognitive-improving effects of memantine, an NMDA receptor antagonist, in some AD patients (Parsons et al 2007). In support of this, AβPP/PS1 mice fed a HFD followed by treatment with memantine saw significant reductions in insulin resistance, neuroinflammation, and cognitive deficits (Ettcheto et al 2018). Alternatively, a HFD has been shown to decrease NMDA receptor subunit GluN2B leading to desensitization that may account for cognitive deficits (Valladolid-Acebes et al 2012).…”