Seizures and Amyloid-β induce similar changes in neuronal network metabolic parameters in mouse hippocampal slices

Abstract

Abstract.Major risk factors for neurodegenerative diseases share brain hypometabolism as one common outcome. In turn, many neurodegenerative pathologies result in brain hypometabolism; both epilepsy and Alzheimer's disease are characterised by disruptions in glucose metabolism. However, the causative link between energy shortage and neuronal pathologies in these diseases has remained elusive. Using realtime brain slice recordings of energy metabolism parameter (NAD(P)H, FAD, pO2 and extracellular glucose) transients in response to network activation, we found that induced epileptic seizures and amyloid-beta peptide both result in similar and longlasting disruptions of neuronal energy metabolism, suggesting a common path of action. In addition, we found that in both cases, subsequent addition of pyruvate, the principal mitochondrial fuel possessing multiple neuroprotective properties, completely normalised the disputed energy state. Our data supports the hypothesis that energy metabolism deficiency underlies the initiation of neurodegenerative diseases.Major risk factors for acquired epilepsy (traumatic brain injury, stroke, viral infection, status epilepticus (Waldbaum and Patel, 2010;Pitkanen et al., 2015) all share hypometabolic brain state as the common outcome; in turn, epileptic patients' also exhibit brain hypometabolism, seen as reduced glucose utilization in FDG-PET analysis (Goffin et al., 2008). To examine whether epileptic activity impairs PeerJ Preprints | https://doi.org/10.7287/peerj.preprints.2521v1 | CC BY 4.0 Open Access |

The vicious circle of hypometabolism in neurodegenerative diseases: Ways and mechanisms of metabolic correction

“…In hippocampal slices, protofibrillar Aβ 1‐42 induced a strong reduction of glucose uptake seen as abated activity‐dependent extracellular glucose transients (Ivanov et al, ), as well as significantly decreased NAD(P)H response overshoot (upper part of biphasic fluorescence response to synaptic stimulation; Ivanov et al, ; Zilberter et al, ) presumably directly related to glycolysis (Ivanov et al, ). Interestingly, however, neither NAD(P)H nor FAD oxidative phase representing mitochondrial processing, nor oxygen consumption changed under Aβ 1‐42 (Ivanov et al, ; Zilberter et al, ). These results indicate impaired glycolysis but an intact mitochondrial function.…”

“…To elucidate the other side of this chicken‐or‐egg question—whether the seizures are capable of lasting disruption of energy metabolism and network excitability—we developed a “seizure model” in hippocampal slices and evaluated the resting‐state network and energy parameters following the recovery from seizures (Ivanov et al, ). We found that a few seizures strongly compromised the energy metabolism of the neuronal network; a phenomenon associated with accumulation of ROS (see also: Azam et al, ; Martinc et al, ) and significantly reduced glucose utilization.…”

“…Similar changes in the NAD(P)H overshoot have also been previously reported in hippocampal slices from pilocarpine‐treated, chronic epileptic rats and from pharmaco‐resistant epileptic patients (Kann et al, ). Interestingly, mitochondrial oxidative metabolism seemed to remain unaltered as the NAD(P)H and FAD oxidation phases as well as oxygen consumption did not change following the seizures (Ivanov et al, ). Thus, the seizures' effect on glucose consumption is rapid and long lasting, likely associated with oxidative stress– and more importantly, is potentially reversible since the reduced glucose consumption following the seizures (as in the case of Aβ effects) was completely restored by subsequent application of pyruvate (Ivanov et al, ).…”

“…Interestingly, mitochondrial oxidative metabolism seemed to remain unaltered as the NAD(P)H and FAD oxidation phases as well as oxygen consumption did not change following the seizures (Ivanov et al, ). Thus, the seizures' effect on glucose consumption is rapid and long lasting, likely associated with oxidative stress– and more importantly, is potentially reversible since the reduced glucose consumption following the seizures (as in the case of Aβ effects) was completely restored by subsequent application of pyruvate (Ivanov et al, ). Interestingly, neither lactate nor β‐hydroxybutyrate could reproduce this pyruvate effect.…”

Chia seeds as a potential cognitive booster in the APP23 Alzheimer’s disease model

“…On the one hand, Aβ alters glucose metabolism, e.g. by reducing glucose uptake into cells 8 . On the other hand, glucose hypometabolism leads to energy deficiency and oxidative stress, which in turn induce Aβ overproduction 9 .…”