Non‐fibrillar β‐amyloid abates spike‐timing‐dependent synaptic potentiation at excitatory synapses in layer 2/3 of the neocortex by targeting postsynaptic AMPA receptors

Department of Neuroscience, Retzius väg 8:A3-417, Karolinska Institutet, S-17177 Stockholm, Sweden.
European Journal of Neuroscience (Impact Factor: 3.18). 05/2006; 23(8):2035-47. DOI: 10.1111/j.1460-9568.2006.04733.x
Source: PubMed


Cognitive decline in Alzheimer's disease (AD) stems from the progressive dysfunction of synaptic connections within cortical neuronal microcircuits. Recently, soluble amyloid beta protein oligomers (Abeta(ol)s) have been identified as critical triggers for early synaptic disorganization. However, it remains unknown whether a deficit of Hebbian-related synaptic plasticity occurs during the early phase of AD. Therefore, we studied whether age-dependent Abeta accumulation affects the induction of spike-timing-dependent synaptic potentiation at excitatory synapses on neocortical layer 2/3 (L2/3) pyramidal cells in the APPswe/PS1dE9 transgenic mouse model of AD. Synaptic potentiation at excitatory synapses onto L2/3 pyramidal cells was significantly reduced at the onset of Abeta pathology and was virtually absent in mice with advanced Abeta burden. A decreased alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/N-methyl-D-aspartate (NMDA) receptor-mediated current ratio implicated postsynaptic mechanisms underlying Abeta synaptotoxicity. The integral role of Abeta(ol)s in these processes was verified by showing that pretreatment of cortical slices with Abeta((25-35)ol)s disrupted spike-timing-dependent synaptic potentiation at unitary connections between L2/3 pyramidal cells, and reduced the amplitude of miniature excitatory postsynaptic currents therein. A robust decrement of AMPA, but not NMDA, receptor-mediated currents in nucleated patches from L2/3 pyramidal cells confirmed that Abeta(ol)s perturb basal glutamatergic synaptic transmission by affecting postsynaptic AMPA receptors. Inhibition of AMPA receptor desensitization by cyclothiazide significantly increased the amplitude of excitatory postsynaptic potentials evoked by afferent stimulation, and rescued synaptic plasticity even in mice with pronounced Abeta pathology. We propose that soluble Abeta(ol)s trigger the diminution of synaptic plasticity in neocortical pyramidal cell networks during early stages of AD pathogenesis by preferentially targeting postsynaptic AMPA receptors.

Download full-text


Available from: Misha Zilberter,
  • Source
    • "Indeed, behavioral tests would not be relevant for such context as the signs of cognitive impairments for this AD model have not been observed before 10 months of age (Minkeviciene et al. 2008). However, we have previously reported significant progressive impairment in spike timing-dependent plasticity in the very same TG mice that were several months younger (Shemer et al. 2006). In this study, we show that the acute Ab 1-42 application strongly reduces the tetanus stimulationinduced LTP, while this toxic effect is completely prevented by the presence of OES. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Deficient energy metabolism and network hyperactivity are the early symptoms of Alzheimer's disease (AD). In this study, we show that administration of exogenous oxidative energy substrates (OES) corrects neuronal energy supply deficiency that reduces the amyloid-beta-induced abnormal neuronal activity in vitro and the epileptic phenotype in AD model in vivo. In vitro, acute application of protofibrillar amyloid-β(1-42) (Aβ(1-42) ) induced aberrant network activity in wild-type hippocampal slices that was underlain by depolarization of both the neuronal resting membrane potential and GABA-mediated current reversal potential. Aβ(1-42) also impaired synaptic function and long-term potentiation. These changes were paralleled by clear indications of impaired energy metabolism, as indicated by abnormal NAD(P)H signaling induced by network activity. However, when glucose was supplemented with OES pyruvate and 3-beta-hydroxybutyrate, Aβ(1-42) failed to induce detrimental changes in any of the above parameters. We administered the same OES as chronic supplementation to a standard diet to APPswe/PS1dE9 transgenic mice displaying AD-related epilepsy phenotype. In the ex-vivo slices we found neuronal sub-populations with significantly depolarized resting and GABA-mediated current reversal potentials, mirroring abnormalities we observed under acute Aβ(1-42) application. Ex-vivo cortex of transgenic mice fed with standard diet displayed signs of impaired energy metabolism, such as abnormal NAD(P)H signaling and strongly reduced tolerance to hypoglycemia. Transgenic mice also possessed brain glycogen levels twofold lower than those of wild-type mice. However, none of the above neuronal and metabolic dysfunctions were observed in transgenic mice fed with the OES-enriched diet. In vivo, dietary OES supplementation abated neuronal hyperexcitability, as the frequency of both epileptiform discharges and spikes was strongly decreased in the APPswe/PS1dE9 mice placed on the diet. Altogether, our results suggest that early AD-related neuronal malfunctions underlying hyperexcitability and energy metabolism deficiency can be prevented by dietary supplementation with native energy substrates. © 2012 International Society for Neurochemistry, J. Neurochem. (2012) 10.1111/jnc.12127.
    Journal of Neurochemistry 12/2012; 125(1). DOI:10.1111/jnc.12127 · 4.28 Impact Factor
  • Source
    • "In the present study, APP/PS1 double transgenic mice overexpressing chimeric mouse/human APP with the Swedish double mutation (K595N and M596L) and human PS1-ΔE9 (deletion of presenilin 1 exon 9) mutation were used [3] [4]. This line is originally maintained in a hybrid C3HeJ C57BL6/ J F1 background and manifests a rapid accumulation of amyloid plaques in the cortex and hippocampus beginning at about 3 months of age [4] [5] [6] [7]. Additionally, these mice exhibit other pathological featured alterations associated with AD [8] [9]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: To investigate the cognitive enhancement effect of WNK, an extracts combination of P. ginseng,  G. biloba, and C. sativus L. and possible mechanisms, 5-month-old APP/PS1 transgenic mice were used in this study. After 3 months of administration, all mice received Morris water maze (MWM) training and a probe test. Mouse brain sections were detected by immunohistochemistry, HE staining, and transmission electron microscopy. MWM results showed significant difference between transgenic mice and nontransgenic littermates (P < 0.05, P < 0.01). WNK-treated mice exhibited enhanced maze performance over the training progression, especially better spatial memory retention in probe test compared to transgenic mice (P < 0.05, P < 0.01) and better spatial learning and memory at the fourth day of MWM test compared to EGB761- (G. biloba extract-) treated ones (P < 0.05). Hippocampal Aβ plaque burden significantly differed between APP/PS1 and littermate mice (P < 0.001), while decreased Aβ plaque appeared in WNK- or EGB761-treated transgenic brains (P < 0.05). Neurodegenerative changes were evident from light microscopic and ultrastructural observations in transgenic brains, which were improved by WNK or EGB761 treatment. These data indicate WNK can reduce the decline in spatial cognition, which might be due to its effects on reducing Aβ plaque formation and ameliorating histopathology and ultrastructure in hippocampus of APP/PS1 mouse brain.
    Evidence-based Complementary and Alternative Medicine 07/2012; 2012:478190. DOI:10.1155/2012/478190 · 1.88 Impact Factor
  • Source
    • "In addition, select sections were stained for the N-terminal human Aβ-specific antibody W02 (Genetics, Switzerland) to visualize diffuse amyloid deposits . Amyloid plaques were examined in septal hippocampal sections using an Olympus microscope at ×10–20 magnification to verify that transgenic animals were expressing amyloid pathology, as described previously (Shemer et al. 2006). Consistent with earlier studies (Garcia-Alloza et al. 2006; Minkeviciene et al. 2009), amyloid plaques only started to build up in 5-month-old APdE9 mice (corresponding to ∼0.1% amyloid plaque load at this age, whereas amyloid load can exceed 20% of the cortical volume in aged APP/PS1 mice). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Amyloid precursor protein transgenic mice modeling Alzheimer's disease display frequent occurrence of seizures peaking at an age when amyloid plaques start to form in the cortex and hippocampus. We tested the hypothesis that numerous reported interactions of amyloid-β with cell surface molecules result in altered excitation-inhibition balance in brain-wide neural networks, eventually leading to epileptogenesis. We examined electroencephalograms (EEGs) and auditory-evoked potentials (AEPs) in freely moving 4-month-old APPswe/PS1dE9 (APdE9) and wild-type (WT) control mice in the hippocampus, cerebral cortex, and thalamus during movement, quiet waking, non-rapid eye movement sleep, and rapid eye movement (REM) sleep. Cortical EEG power was higher in APdE9 mice than in WT mice over a broad frequency range (5-100 Hz) and during all 4 behavioral states. Thalamic EEG power was also increased but in a narrower range (10-80 Hz). Furthermore, APdE9 mice displayed augmented cortical and thalamic AEPs. While power and theta-gamma modulation were preserved in the APdE9 hippocampus, REM sleep-related phase shift of theta-gamma modulation was altered. Our data suggest that at the early stage of amyloid pathology, cortical principal cells become hyperexcitable and via extensive cortico-thalamic connection drive thalamic cells. Minor hippocampal changes are most likely secondary to abnormal entorhinal input.
    Cerebral Cortex 05/2012; 23(5). DOI:10.1093/cercor/bhs105 · 8.67 Impact Factor
Show more