Astrocyte and glutamate involvement in the pathogenesis of epilepsy in Alzheimer's disease

Abstract

Alzheimer's disease (AD) can increase the risk of epilepsy by up to 10-fold compared to healthy age-matched controls. However, the pathological mechanisms that underlie this increased risk are poorly understood. Because disruption in brain glutamate homeostasis has been implicated in both AD and epilepsy, this might play a mechanistic role in the pathogenesis of epilepsy in AD. Prior to the formation of amyloid beta (Aβ) plaques, the brain can undergo pathological changes as a result of increased production of amyloid precursor protein (APP) and Aβ oligomers. Impairments in the glutamate uptake ability of astrocytes due to astrogliosis are hypothesized to be an early event occurring before Aβ plaque formation. Astrogliosis may increase the susceptibility to epileptogenesis of the brain via accumulation of extracellular glutamate and resulting excitotoxicity. Here we hypothesize that Aβ oligomers and proinflammatory cytokines can cause astrogliosis and accumulation of extracellular glutamate, which then contribute to the pathogenesis of epilepsy in AD. In this review article, we consider the evidence supporting a potential role of dysfunction of the glutamateglutamine cycle and the astrocyte in the pathogenesis of epilepsy in AD.

Carbonic Anhydrases as Potential Targets Against Neurovascular Unit Dysfunction in Alzheimer’s Disease and Stroke

“…Despite the differential contributions of the glymphatic system and the IPAD pathway to the clearance of cerebral fluids and waste material are not completely grasped, it is accepted that astrocytes play a pivotal role in the exchange of fluids, based on studies showing that, in AQP4 KO mice, cerebrospinal fluid influx as well as CNS clearance were decreased ( Iliff et al, 2012 ; Braun and Iliff, 2020 ). Another essential function of astrocytes is glutamate uptake and release, which is very important for the maintenance of CNS homeostasis ( Dejakaisaya et al, 2021 ; van Putten et al, 2021 ; Verkerke et al, 2021 ). Astrocytes also have a critical role in the brain antioxidant system maintenance and in the production of glutathione, an important modulator of oxidative stress and aging ( Bains and Shaw, 1997 ; Venkateshappa et al, 2012 ; Howarth et al, 2017 ; Verkerke et al, 2021 ).…”

An Unbalanced Synaptic Transmission: Cause or Consequence of the Amyloid Oligomers Neurotoxicity?

“…A relevant factor in enhancing neuronal excitability is represented by inflammation, which is a common feature of both AD and epilepsy [201]. In a recent report, Dejakaisaya and co-authors [202] hypothesized that the disruption of brain glutamate homeostasis, in which astrocytes play a key role, could constitute the link between AD and epilepsy. These authors speculate that the impairment in glutamate uptake is an early event occurring before plaque deposition and due to astrogliosis, which in turn enhances the susceptibility to epileptogenesis through the accumulation of extracellular glutamate and consequent excitotoxicity.…”

The Use of Fourier Transform Infrared Microspectroscopy for the Determination of Biochemical Anomalies of the Hippocampal Formation Characteristic for the Kindling Model of Seizures

“…Proteins of the β-sheet structure may cause astrogliosis and accumulation of extracellular glutamate, which contribute to seizure progress. 34 In turn, the modification of the protein conformation may be induced by the products of lipid peroxidation associated, among others, with oxidative stress promoted by reactive oxygen species. 33 , 35 Lipid peroxidation may manifest in some structural changes of these molecules, which can be measured indirectly through the analysis of the ratio of intensities of 2924 and 2955 cm –1 absorption bands originating from the asymmetric stretchings of CH 2 and CH 3 groups, respectively.…”