Alterations in Cerebral Cortical Glucose and Glutamine Metabolism Precedes Amyloid Plaques in the APPswe/PSEN1dE9 Mouse Model of Alzheimer’s Disease

Abstract

Alterations in brain energy metabolism have been suggested to be of fundamental importance for the development of Alzheimer's disease (AD). However, specific changes in brain energetics in the early stages of AD are poorly known. The aim of this study was to investigate cerebral energy metabolism in the APPswe/PSEN1dE9 mouse prior to amyloid plaque formation. Acutely isolated cerebral cortical and hippocampal slices of 3-month-old APPswe/PSEN1dE9 and wild-type control mice were incubated in media containing [U-C]glucose, [1,2-C]acetate or [U-C]glutamine, and tissue extracts were analyzed by mass spectrometry. The ATP synthesis rate of isolated whole-brain mitochondria was assessed by an on-line luciferin-luciferase assay. Significantly increased C labeling of intracellular lactate and alanine and decreased tricarboxylic acid (TCA) cycle activity were observed from cerebral cortical slices of APPswe/PSEN1dE9 mice incubated in media containing [U-C]glucose. No changes in glial [1,2-C]acetate metabolism were observed. Cerebral cortical slices from APPswe/PSEN1dE9 mice exhibited a reduced capacity for uptake and oxidative metabolism of glutamine. Furthermore, the ATP synthesis rate tended to be decreased in isolated whole-brain mitochondria of APPswe/PSEN1dE9 mice. Thus, several cerebral metabolic changes are evident in the APPswe/PSEN1dE9 mouse prior to amyloid plaque deposition, including altered glucose metabolism, hampered glutamine processing and mitochondrial dysfunctions.

<p>Circulating Glutamine and Alzheimer’s Disease: A Mendelian Randomization Study</p>

“…This implies that alterations in glutamine metabolism may be early transformations in the pathogenesis of Alzheimer's disease. 38 Since the accumulation of amyloid plaques has been associated with inflammation, oxidative stress and mitochondrial dysfunction, 39 perhaps exogenous glutamine can protect against this in the early phrases of the disease.…”

Impaired Hippocampal Glutamate and Glutamine Metabolism in the db/db Mouse Model of Type 2 Diabetes Mellitus

“…The reduced labeling observed from incubations with [U- 13 C]glutamine could arise from reduced neuronal TCA cycle activity, as recently shown in a mouse model of early AD [19]. If the TCA cycle activity is decreased, the need for introduction of α -ketoglutarate derived from glutamine through glutamate likewise falls, leading to reduced 13 C labeling.…”

“…Acutely isolated brain slices were prepared as previously described [19, 20]. Briefly, animals were euthanized by cervical dislocation and the brain excised into ice-cold artificial cerebrospinal fluid (ACSF) containing the following in mM: NaCl 128, NaHCO 3 25, KCl 3, CaCl 2 2, MgSO 4 1.2, and KH 2 PO 4 0.4, pH = 7.4.…”

“…Determination of quantitative amounts of amino acids from brain slice extracts was assessed by reversed-phase high-performance liquid chromatography (HPLC) using precolumn o-phthalaldehyde derivatization and fluorescent detection (excitation λ = 338 nm, emission λ = 390 nm) as previously described [19]. The amounts of lactate released from the brain slices to the incubation medium were assessed using an enzymatic kit, based on the coupled reactions between lactate dehydrogenase and alanine aminotransferase, from Boehringer Mannheim/R-Biopharm AG (Darmstadt, Germany) according to the manufacturer's instructions.…”

Circulating glutamine and Alzheimer’s disease: a Mendelian randomization study

“…Moreover, Anderson et al (2017) observed that reduced glutamine uptake and hampered oxidative glutamine metabolism precede amyloid plaque formation in APPswe/PSEN1dE9 mice compared to controls. This implies that alterations in glutamine metabolism may be early transformations in the pathogenesis of Alzheimer's disease [35]. Since the accumulation of amyloid plaques has been associated with inflammation, oxidative stress and mitochondrial dysfunction [36], perhaps exogenous glutamine can protect against this in the early phrases of the disease.…”