Disruption of Glucose Metabolism in Aged Octodon degus: A Sporadic Model of Alzheimer's Disease.

Pedro Cisternas,Paulina Salazar,Camila Gherardelli,Nibaldo C Inestrosa

doi:10.3389/fnint.2021.733007

Abstract

Alzheimer's disease is a progressive neurodegenerative disorder and the most common cause of dementia. Although transgenic Alzheimer's disease (AD) animal models have greatly contributed to our understanding of the disease, therapies tested in these animals have resulted in a high rate of failure in preclinical trials for AD. A promising model is Octodon degus (degu), a Chilean rodent that spontaneously develops AD-like neuropathology. Previous studies have reported that, during aging, degus exhibit a progressive decline in cognitive function, reduced neuroinflammation, and concomitant increases in the number and size of amyloid β (Aβ) plaques in several brain regions. Importantly, in humans and several AD models, a correlation has been shown between brain dysfunction and neuronal glucose utilization impairment, a critical aspect considering the high-energy demand of the brain. However, whether degus develop alterations in glucose metabolism remains unknown. In the present work, we measured several markers of glucose metabolism, namely, glucose uptake, ATP production, and glycolysis and pentose phosphate pathway (PPP) flux, in hippocampal slices from degus of different ages. We found a significant decrease in hippocampal glucose metabolism in aged degus, caused mainly by a drop in glucose uptake, which in turn, reduced ATP synthesis. Moreover, we observed a negative correlation between age and PPP flux. Together, our data further support the use of degus as a model for studying the neuropathology involved in sporadic AD-like pathology and as a potentially valuable tool in the search for effective treatments against the disease.

Highlights

Alzheimer’s disease is a progressive neurodegenerative disease that culminates with the loss of cognitive functions (Serrano-Pozo et al, 2011; Dubois et al, 2016)
To evaluate whether the observed disturbances in glucose uptake are caused by alterations in glucose transporters (Gluts), we measured the mRNA expression of hippocampal Glut 1, 3, and 4
Cerebral glucose hypometabolism has been used as an early-stage biomarker prior to the onset of clinical symptoms in patients with Alzheimer’s disease (AD) (Mosconi et al, 2008a; Bulleid, 2012; Johnson et al, 2020; Lu et al, 2020; Tams et al, 2021; Zhang et al, 2021)

Summary

Introduction

Alzheimer’s disease is a progressive neurodegenerative disease that culminates with the loss of cognitive functions (Serrano-Pozo et al, 2011; Dubois et al, 2016). Alzheimer’s disease (AD) is characterized by the presence of (Aβ)-containing extracellular deposits and intracellular aggregations of hyperphosphorylated tau in the brains of affected patients (Deture and Dickson, 2019; Long and Holtzman, 2019). To ensure proper function and meet its high energetic requirements, the brain requires a continuous supply of glucose, a task that is mainly performed by glucose transporters (Gluts) (Duelli and Kuschinsky, 2001; Shah et al, 2012). A reduction in Glut expression has been observed in the brains of patients with AD and in transgenic mouse models of AD, which exacerbates the pathology by increasing Aβ load and tau phosphorylation, accelerating cognitive impairment and promoting neuronal dysfunction (Liu et al, 2008; Shah et al, 2012; Winkler et al, 2015). Strategies for restoring glucose have been shown to be protective against Aβ toxicity (Niccoli et al, 2016; Cisternas et al, 2019)

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Results

Conclusion