Dietary energy substrates reverse early neuronal hyperactivity in a mouse model of Alzheimer's disease

Abstract

Deficient energy metabolism and network hyperactivity are the early symptoms of Alzheimer's disease (AD). In this study, we show that administration of exogenous oxidative energy substrates (OES) corrects neuronal energy supply deficiency that reduces the amyloid-beta-induced abnormal neuronal activity in vitro and the epileptic phenotype in AD model in vivo. In vitro, acute application of protofibrillar amyloid-b 1-42 (Ab 1-42 ) induced aberrant network activity in wild-type hippocampal slices that was underlain by depolarization of both the neuronal resting membrane potential and GABA-mediated current reversal potential. Ab 1-42 also impaired synaptic function and long-term potentiation. These changes were paralleled by clear indications of impaired energy metabolism, as indicated by abnormal NAD(P)H signaling induced by network activity. However, when glucose was supplemented with OES pyruvate and 3-beta-hydroxybutyrate, Ab 1-42 failed to induce detrimental changes in any of the above parameters.We administered the same OES as chronic supplementation to a standard diet to APPswe/PS1dE9 transgenic mice displaying AD-related epilepsy phenotype. In the ex-vivo slices, we found neuronal subpopulations with significantly depolarized resting and GABA-mediated current reversal potentials, mirroring abnormalities we observed under acute Ab 1-42 application. Ex-vivo cortex of transgenic mice fed with standard diet displayed signs of impaired energy metabolism, such as abnormal NAD(P)H signaling and strongly reduced tolerance to hypoglycemia. Transgenic mice also possessed brain glycogen levels twofold lower than those of wild-type mice. However, none of the above neuronal and metabolic dysfunctions were observed in transgenic mice fed with the OES-enriched diet. In vivo, dietary OES supplementation abated neuronal hyperexcitability, as the frequency of both epileptiform discharges and spikes was strongly decreased in the APPswe/PS1dE9 mice placed on the diet. Altogether, our results suggest that early AD-related neuronal malfunctions underlying hyperexcitability and energy metabolism deficiency can be prevented by dietary supplementation with native energy substrates.

Pyruvate prevents the development of age-dependent cognitive deficits in a mouse model of Alzheimer's disease without reducing amyloid and tau pathology

“…Hyperexcitability has been described in AD models and patients and can be the trigger for glutamatergic overstimulation (Davis et al, 2014;Friedman et al, 2012;Noebels, 2011;Palop and Mucke, 2009). Pyruvate, in association with 3-beta-hydroxybutyrate, has been shown to reduce epileptiform activity in a AD mouse model (Zilberter et al, 2013). In line with this set of data, we observed a significant reduction of spontaneous synaptic activity as indicated by decreased [Ca 2 + ] i spike frequency in pyruvate-treated 3xTg-AD cultured neurons (Fig.…”

“…Metabolic dysfunction and hyperexcitability have been shown to be causally related and administration of pyruvate in combination with 3-beta-hydroxybutyrate has been described to reduce epileptiform activity in a preclinical AD model (Kudin et al, 2009;Pan et al, 2008;Waldbaum and Patel, 2010;Zilberter et al, 2013). Given the enhanced neuronal excitability observed in 3xTg-AD mice in vivo (Davis et al, 2014), we explored whether the phenomenon could be attenuated by pyruvate.…”

Intermittent metabolic switching, neuroplasticity and brain health

“…Mechanisms by which IMS may lessen neuropathology and ameliorate cognitive deficits in AD mice include a reduction of amyloidogenic enzymatic processing of APP, suppression of inflammation, constraint of neuronal hyperexcitability and upregulation of adaptive neuronal stress-resistance pathways (for example, neurotrophic factors, antioxidant defences and nuclear and mitochondrial sirtuins) 6,141,142 . Ketones may counteract AD pathogenesis because a ketone ester diet that elevates BHB more than tenfold lessens Aβ and tau pathologies and ameliorates behavioural abnormalities in 3xTg-AD mice 143 .…”

Regulation of pyruvate metabolism and human disease

“…One way Aβ exerts neurotoxic effects is by increasing ROS production through activation of NAPDH oxidase [202]. Increased ROS, in turn, upregulates expression of hypoxia inducible factor-1α (HIF-1α) which stabilizes expression of BACE1 as well as increases the activity of PDK1, thereby reducing PDH activity and reducing mitochondrial pyruvate flux through oxidative phosphorylation [203]. Furthermore, peroxidation of lipids present in the brain creates a toxic product called acrolein, which is a potent inhibitor of lipoate-containing proteins, such as PDH [180, 204, 205].…”

“…In one study, exogenous administration of pyruvate and 3-beta-hydroxybutyrate directly into the cerebrospinal fluid was shown to ablate excitatory neurotoxicity and corrected neuronal energy deficiency in a mouse model of Alzheimer’s disease [203]. In astrocytes, the ATP generated by aerobic glycolysis is used to fuel glutamate uptake by excitatory amino acid transporter [192, 235, 236].…”