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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 tricarboxylic acid (TCA) cycle metabolism mapped by stable 13 C isotope tracing. Particularly, reduced astrocyte TCA cycle activity and decreased glutamine synthesis led to hampered neuronal GABA synthesis in the 5xFAD hippocampus. In contrast, the cerebral cortex of 5xFAD mice displayed an elevated capacity for oxidative glucose metabolism, which may suggest a metabolic compensation in this brain region. 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 selectively impaired 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 dysfunctions in AD., (© 2021. The Author(s).)

Over 70 million European pregnant women are smokers during their child-bearing years. Consumption of tobacco-containing products during pregnancy is associated with several negative behavioral outcomes for the offspring, including a higher susceptibility for the development of attention-deficit/hyperactive disorder (ADHD). In efforts to minimize fetal exposure to tobacco smoke, many women around the world switch to nicotine replacement therapies (NRTs) during the gestational period; however, prenatal nicotine exposure (PNE) in any form has been associated with alterations in cognitive processes, including learning, memory, and attention. These processes are controlled by glutamatergic signaling of hippocampal pyramidal neurons within the CA1 region, suggesting actions of nicotine on glutamatergic transmission in this region if present prenatally. Accordingly, we aimed to investigate hippocampal glutamatergic function following PNE treatment in NMRI mice employing molecular, cellular electrophysiology, and pharmacological approaches, as well as to evaluate cognition in the rodent continuous performance task (rCPT), a recently developed mouse task allowing assessment of learning, attention, and impulsivity. PNE induced increases in the expression levels of mRNA coding for different glutamate receptors and subunits within the hippocampus. Functional alterations in AMPA and NMDA receptors on CA1 pyramidal neurons of PNE mice were suggestive of higher GluA2-lacking and lower GluN2A-containing receptors, respectively. Finally, PNE was associated with reduced learning, attention, and enhanced impulsivity in the rCPT. Alterations in glutamatergic functioning in CA1 neurons parallel changes seen in the spontaneously hypertensive rat ADHD model and likely contribute to the lower cognitive performance in the rCPT.