Hippocampal Disruptions of Synaptic and Astrocyte Metabolism are Primary Events of Early Amyloid Pathology in the 5xFAD Mouse Model of Alzheimer's Disease

Jens V Andersen,Heikki Tanila,Ramon Sun,Filip Polli,Marta Castillo,Kristi Kohlmeier,Helle Sønderby Waagepetersen,Matthew S Gentry,Matthias Mann,Sofie Christensen,Kristine Freude,Niels Skotte,Emil Westi,Blanca Aldana,Kia Markussen,Henriette Haukedal,Mohammad Shabani,Arne Schousboe

doi:10.2139/ssrn.3838989

Abstract

Alzheimer’s disease (AD) is an unremitting neurodegenerative disorder characterized by cerebral amyloid-β (Aβ) accumulation and gradual decline in cognitive function. Changes in brain energy metabolism arise in the preclinical phase of AD, suggesting an important metabolic component of early AD pathology. Neurons and astrocytes function in close metabolic collaboration, which is essential for the recycling of neurotransmitters in the synapse. However, this crucial metabolic interplay during the early stages of AD development has not been sufficiently investigated. Here, we provide an integrative analysis of cellular metabolism during the early stages of Aβ accumulation in the cerebral cortex and hippocampus of the 5xFAD mouse model of AD. Our electrophysiological examination revealed an increase in spontaneous excitatory signaling in the 5xFAD hippocampus. This hyperactive neuronal phenotype coincided with decreased hippocampal TCA cycle metabolism mapped by stable 13C isotope tracing. Particularly, reduced astrocyte TCA cycle activity led to decreased glutamine synthesis, in turn hampering neuronal GABA synthesis in the 5xFAD hippocampus. In contrast, the cerebral cortex of 5xFAD mice displayed an elevated capacity for oxidative glucose metabolism suggesting a metabolic compensation. We found limited changes when we explored the brain proteome and metabolome of the 5xFAD mice, supporting that the functional metabolic disturbances between neurons and astrocytes are early primary events in AD pathology. In addition, synaptic mitochondrial and glycolytic function was impaired selectively in the 5xFAD hippocampus, whereas non-synaptic mitochondrial function was maintained. These findings were supported by ultrastructural analyses demonstrating disruptions in mitochondrial morphology, particularly in the 5xFAD hippocampus. Collectively, our study reveals complex regional and cell-specific metabolic adaptations, in the early stages of amyloid pathology, which may be fundamental for the progressing synaptic dysfunction in AD.

Highlights

Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by cerebral accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles [1, 2]
In the 5xFAD hippocampus, we found dysfunctional excitatory neuronal signaling, hampered cellular metabolism, and alterations in the proteome
Synapses and mitochondria were affected at the ultrastructural level in both the cerebral cortex and hippocampus of the 5xFAD mice, but this was only functionally reflected in the hippocampus, suggesting strong initial metabolic impacts of early amyloid pathology in this region

Summary

Introduction

Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by cerebral accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles [1, 2]. Aβ deposition leads to dysfunctional synaptic signaling and neuronal death, progressing over decades before clinical symptoms of dementia arise [2, 3]. This long preclinical phase of AD has been described as the window of potential disease intervention [2, 4]. Understanding the early mechanisms behind AD pathology is imperative in finding a treatment. Differential changes in regional brain energy metabolism already emerge in the preclinical phase of AD, suggesting an important metabolic component of early AD pathology [6, 7]

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Conclusion