Altered metabolic pathways in a transgenic mouse model suggest mechanistic role of amyloid precursor protein overexpression in Alzheimer's disease.

INTRODUCTION: The mechanistic role of amyloid precursor protein (APP) in Alzheimer's disease (AD) remains unclear. OBJECTIVES: Here, we aimed to identify alterations in cerebral metabolites and metabolic pathways in cortex, hippocampus and serum samples from Tg2576 mice, a widely used mouse model of AD. METHODS: Metabolomic profilings using liquid chromatography-mass spectrometry were performed and analysed with MetaboAnalyst and weighted correlation network analysis (WGCNA). RESULTS: Expressions of 11 metabolites in cortex, including hydroxyphenyllactate-linked to oxidative stress-and phosphatidylserine-lipid metabolism-were significantly different between Tg2576 and WT mice (false discovery rate < 0.05). Four metabolic pathways from cortex, including glycerophospholipid metabolism and pyrimidine metabolism, and one pathway (sulphur metabolism) from hippocampus, were significantly enriched in Tg2576 mice. Network analysis identified five pathways, including alanine, aspartate and glutamate metabolism, and mitochondria electron transport chain, that were significantly correlated with AD genotype. CONCLUSIONS: Changes in metabolite concentrations and metabolic pathways are present in the early stage of APP pathology, and may be important for AD development and progression.

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

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 (Aß) plaques, the brain can undergo pathological changes as a result of increased production of amyloid precursor protein (APP) and Aß oligomers. Impairments in the glutamate uptake ability of astrocytes due to astrogliosis are hypothesized to be an early event occurring before Aß plaque formation. Astrogliosis may increase the susceptibility to epileptogenesis of the brain via accumulation of extracellular glutamate and resulting excitotoxicity. Here we hypothesize that Aß 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 glutamate-glutamine cycle and the astrocyte in the pathogenesis of epilepsy in AD.

Structure-Based Identification and Characterization of Inhibitors of the Epilepsy-Associated KNa1.1 (KCNT1) Potassium Channel.

Drug-resistant epileptic encephalopathies of infancy have been associated with KCNT1 gain-of-function mutations, which increase the activity of KNa1.1 sodium-activated potassium channels. Pharmacological inhibition of hyperactive KNa1.1 channels by quinidine has been proposed as a stratified treatment, but mostly this has not been successful, being linked to the low potency and lack of specificity of the drug. Here we describe the use of a previously determined cryo-electron microscopy-derived KNa1.1 structure and mutational analysis to identify how quinidine binds to the channel pore and, using computational methods, screened for compounds predicated to bind to this site. We describe six compounds that inhibited KNa1.1 channels with low- and sub-micromolar potencies, likely also through binding in the intracellular pore vestibule. In hERG inhibition and cytotoxicity assays, two compounds were ineffective. These may provide starting points for the development of new pharmacophores and could become tool compounds to study this channel further.