Supragranular Pyramidal Cells Exhibit Early Metabolic Alterations in the 3xTg-AD Mouse Model of Alzheimer's Disease.

Juliette Piquet,Rodrigo Lerchundi,Émilie Faivre,Régine Hepp,Bruno Cauli,Elvire Guiot,Juliette Le Douce,Xavier Toussay,Gilles Bonvento

doi:10.3389/fncel.2018.00216

Abstract

The impairment of cerebral glucose utilization is an early and predictive biomarker of Alzheimer’s disease (AD) that is likely to contribute to memory and cognition disorders during the progression of the pathology. Yet, the cellular and molecular mechanisms underlying these metabolic alterations remain poorly understood. Here we studied the glucose metabolism of supragranular pyramidal cells at an early presymptomatic developmental stage in non-transgenic (non-Tg) and 3xTg-AD mice, a mouse model of AD replicating numerous hallmarks of the disease. We performed both intracellular glucose imaging with a genetically encoded fluorescence resonance energy transfer (FRET)-based glucose biosensor and transcriptomic profiling of key molecular elements of glucose metabolism with single-cell multiplex RT-PCR (scRT-mPCR). We found that juvenile pyramidal cells exhibit active glycolysis and pentose phosphate pathway at rest that are respectively enhanced and impaired in 3xTg-AD mice without alteration of neuronal glucose uptake or transcriptional modification. Given the importance of glucose metabolism for neuronal survival, these early alterations could initiate or at least contribute to the later neuronal dysfunction of pyramidal cells in AD.

Highlights

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and memory loss
We used a genetically encoded fluorescence resonance energy transfer (FRET)-based glucose biosensor (Deuschle et al, 2005; Takanaga et al, 2008; Bittner C.X. et al, 2010) to investigate the uptake and fate of glucose at a cellular resolution and singlecell multiplex RT-PCR to determine the expression profiles of key elements of glucose metabolism of pyramidal cells. We report that both glycolysis and pentose phosphate pathways are active in juvenile pyramidal cells at rest
We evaluated the importance of the pentose phosphate shunt in the metabolism of pyramidal cells and thought to determine whether it is altered in 3xTg-AD pyramidal cells

Summary

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and memory loss. The visualization by 18-fluoro-2-deoxy-Dglucose positron emission tomography of a decreased cerebral glucose utilization occurring in specific brain regions is one of the earliest functional signs of AD (Small et al, 2000; Dubois et al, 2016) It aggravates with the disease progression and even predicts the neuropathological diagnosis of AD (Mosconi, 2005; Mosconi et al, 2010). The most vulnerable brain regions to Aβ deposition corresponds to areas where glucose is physiologically used beside its role as a substrate for oxidative phosphorylation in spite of oxygen availability (Vaishnavi et al, 2010; Vlassenko et al, 2010) This non-oxidative glucose utilization is Pyramidal Cell’s Glucose Metabolism referred to as “aerobic glycolysis” and includes the glycolysis itself, the pentose phosphate shunt and the glycogen synthesis. These glucose metabolic pathways are highly compartmentalized between neurons and glial cells, glycolysis, and glycogen synthesis occurring mainly in astrocytes (Allaman et al, 2011; Fernandez-Fernandez et al, 2012)

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