Amyloid β-Peptide Impairs Glucose Transport in Hippocampal and Cortical Neurons: Involvement of Membrane Lipid Peroxidation

Abstract

A deficit in glucose uptake and a deposition of amyloid beta-peptide (A beta) each occur in vulnerable brain regions in Alzheimer's disease (AD). It is not known whether mechanistic links exist between A beta deposition and impaired glucose transport. We now report that A beta impairs glucose transport in cultured rat hippocampal and cortical neurons by a mechanism involving membrane lipid peroxidation. A beta impaired 3H-deoxy-glucose transport in a concentration-dependent manner and with a time course preceding neurodegeneration. The decrease in glucose transport was followed by a decrease in cellular ATP levels. Impairment of glucose transport, ATP depletion, and cell death were each prevented in cultures pretreated with antioxidants. Exposure to FeSO4, an established inducer of lipid peroxidation, also impaired glucose transport. Immunoprecipitation and Western blot analyses showed that exposure of cultures to A beta induced conjugation of 4-hydroxynonenal (HNE), an aldehydic product of lipid peroxidation, to the neuronal glucose transport protein GLUT3. HNE induced a concentration-dependent impairment of glucose transport and subsequent ATP depletion. Impaired glucose transport was not caused by a decreased energy demand in the neurons, because ouabain, which inhibits Na+/K(+)-ATPase activity and thereby reduces neuronal ATP hydrolysis rate, had little or no effect on glucose transport. Collectively, the data demonstrate that lipid peroxidation mediates A beta-induced impairment of glucose transport in neurons and suggest that this action of A beta may contribute to decreased glucose uptake and neuronal degeneration in AD.

Effects of Peroxisome Proliferator-Activated Receptor Gamma Agonists on Brain Glucose and Glutamate Transporters after Stress in Rats

“…The fact that the effects observed here were seen on an enriched membrane preparation (synaptosomes) suggests that this may be the case in stress-induced decrease in glucose uptake. The second possible mechanism for the inhibitory stress effects on glucose uptake is the oxidative damage of GLUT-3 evidenced by conjugation of 4-hydroxynonenal (HNE) (Mark et al, 1997) or other lipid peroxidation products released in brain in the same stress model used in this paper (daily immobilization for 6 h during 7 days) (Reagan et al, 2000). This has also been seen in other settings such as cultured hippocampal neurons exposed to Abeta (increased HNE production and conjugation to GLUT-3) (Mark et al, 1997).…”

“…The second possible mechanism for the inhibitory stress effects on glucose uptake is the oxidative damage of GLUT-3 evidenced by conjugation of 4-hydroxynonenal (HNE) (Mark et al, 1997) or other lipid peroxidation products released in brain in the same stress model used in this paper (daily immobilization for 6 h during 7 days) (Reagan et al, 2000). This has also been seen in other settings such as cultured hippocampal neurons exposed to Abeta (increased HNE production and conjugation to GLUT-3) (Mark et al, 1997). In the stress model used here, the production of oxidative and nitrosative mediators and the accumulation of lipid peroxidation markers in the brain have been widely documented (Liu et al, 1996;Madrigal et al, 2001).…”

“…The reported decrease in glucose uptake mediated by stress or by high levels of GCs could place neurons in an energy-compromised environment, which could detrimentally affect neuronal responsiveness to pathophysiological events. In fact, glucose transport impairment precedes ATP depletion in brain, increasing neuronal vulnerability to excitotoxicity by compromising function of ion-motive ATPases (Mark et al, 1995), as it has been seen to occur in some neurodegenerative processes such Ab-induced toxicity, schizophrenia and others (Novelli et al, 1988;Kalaria and Harik, 1989;Sims, 1990;Mark et al, 1997;McDermott and De Silva, 2005) in which the reduction in glucose uptake occurs as an early step in the disease process prior to neuronal degeneration (Pettegrew et al, 1994;Reiman et al, 1996). On the other hand, GCs promote reduction in ATP levels (Tombaugh and Sapolsky, 1992;Lawrence and Sapolsky, 1994).…”

Selective Antibody-Induced Cholinergic Cell and Synapse Loss Produce Sustained Hippocampal and Cortical Hypometabolism with Correlated Cognitive Deficits

“…Interestingly, this hypothesis is further supported by findings that transgenic mice overexpressing human APP exhibit reductions in cerebral glucose metabolism (32). In addition, human APP expression in hippocampal and cortical neurons impairs glucose transport and suppresses ATP production by a mechanism involving membrane lipid peroxidation (49). Overall, the results reported in this study strengthen the argument that APP processing and energy metabolism in the brain are functionally related, and modulation of APP processing resulting from impaired energy metabolism could play a significant role in the pathogenesis of AD.…”

Calorie restriction up-regulates the plasma membrane redox system in brain cells and suppresses oxidative stress during aging

“…The proteins and lipids involved in these functions of the PM are susceptible to oxidative modifications that may contribute to the dysfunction and degeneration of neurons that occur in aging and neurodegenerative disorders (37). For example, lipid peroxidation and oxidative modifications of PM ion-motive ATPases, glucose transporters, and G protein-coupled receptor signaling are implicated in the pathogenesis of Alzheimer's disease (38)(39)(40). The PMRS, which includes CoQ and multiple redox enzymes (Fig.…”