Alzheimer β-amyloid blocks epileptiform activity in hippocampal neurons (original) (raw)
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Brain Research, 2010
Diffusible oligomeric assemblies of the amyloid β-protein (Aβ) could be the primary factor in the pathogenic pathway leading to Alzheimer's disease (AD). Converging lines of evidence support the notion that AD begins with subtle alterations in synaptic efficacy, prior to the occurrence of extensive neuronal degeneration. Recently, however, a shared or overlapping pathogenesis for AD and epileptic seizures occurred as aberrant neuronal hyperexcitability, as well as nonconvulsive seizure activity were found in several different APP transgenic mouse lines. This generated a renewed attention to the well-known comorbidity of AD and epilepsy and interest in how Aβ oligomers influence neuronal excitability. In this study therefore, we investigated the effect of various in vitro-aged Aβ(1-42) oligomer solutions on the perforant pathway-evoked field potentials in the ventral hippocampal dentate gyrus in vivo. Firstly, Aβ oligomer solutions (1 μl, 200 μM) which had been aggregated in vitro for 0, 24 or 72 h were injected into the hippocampus of urethane-anesthetized rats, in parallel with in vitro physico-chemical characterization of Aβ oligomerization (atomic force microscopy, thioflavin-T fluorescence). We found a marked increase of hippocampal population spike (pSpike) after injection of the 24-h Aβ oligomer solution and a decrease of the pSpike amplitude after injection of the 72-h Aβ oligomer. Since urethane anesthesia affects the properties of hippocampal evoked potentials, we repeated the injection of these two Aβ oligomer solutions in awake, freely moving animals. Evoked responses to perforant pathway stimulation revealed a 70% increase of pSpike amplitude 50 min after the 24-h Aβ oligomer injection and a 55% decrease after the 72-h Aβ oligomer injection. Field potentials, that reflect
Amyloid -Induced Neuronal Hyperexcitability Triggers Progressive Epilepsy
Journal of Neuroscience, 2009
Alzheimer's disease is associated with an increased risk of unprovoked seizures. However, the underlying mechanisms of seizure induction remain elusive. Here, we performed video-EEG recordings in mice carrying mutant human APPswe and PS1dE9 genes (APdE9 mice) and their wild-type littermates to determine the prevalence of unprovoked seizures. In two recording episodes at the onset of amyloid  (A) pathogenesis (3 and 4.5 months of age), at least one unprovoked seizure was detected in 65% of APdE9 mice, of which 46% had multiple seizures and 38% had a generalized seizure. None of the wild-type mice had seizures. In a subset of APdE9 mice, seizure phenotype was associated with a loss of calbindin-D28k immunoreactivity in dentate granular cells and ectopic expression of neuropeptide Y in mossy fibers. In APdE9 mice, persistently decreased resting membrane potential in neocortical layer 2/3 pyramidal cells and dentate granule cells underpinned increased network excitability as identified by patch-clamp electrophysiology. At stimulus strengths evoking single-component EPSPs in wild-type littermates, APdE9 mice exhibited decreased action potential threshold and burst firing of pyramidal cells. Bath application (1 h) of A1-42 or A25-35 (proto-)fibrils but not oligomers induced significant membrane depolarization of pyramidal cells and increased the activity of excitatory cell populations as measured by extracellular field recordings in the juvenile rodent brain, confirming the pathogenic significance of bath-applied A (proto-)fibrils. Overall, these data identify fibrillar A as a pathogenic entity powerfully altering neuronal membrane properties such that hyperexcitability of pyramidal cells culminates in epileptiform activity.
Journal of Alzheimer's disease : JAD, 2011
It is believed that amyloid-β peptide (Aβ), in its aggregated-oligomeric state, constitutes one of the neurotoxic factors involved in the pathogenesis of Alzheimer's disease. With the objective of studying a potential role of the peptide on synaptic transmission, we studied the effect of soluble Aβ(1-40) on synaptic transmission in rat hippocampal neurons. Neurons incubated with 500 nM of Aβ(1-40) peptide for 3 days presented higher levels of intracellular calcium transients, as evaluated by fluorimetric techniques. These effects of Aβ were time and concentration dependent and were accompanied by increases in glutamatergic (0.8±0.2 Hz to 2.9±0.6 Hz), but not GABAergic, transmission. The analysis of pharmacologically isolated currents in treated neurons showed increases in both AMPA- and NMDA-mediated currents as compared to control. The effects of the peptide on the frequency of synaptic currents correlated well with increases in the number of SV2 puncta and of FM1-43 destaining...
Soluble Aβ oligomers impair hippocampal LTP by disrupting glutamatergic/GABAergic balance
Neurobiology of Disease, 2016
Epileptic activity may be more prevalent in early stage Alzheimer's disease (AD) than previously believed. Several studies report spontaneous seizures and interictal discharges in mouse models of AD undergoing age-related Aβ accumulation. The mechanism by which Aβ-induced neuronal excitability can trigger epileptiform activity remains unknown. Here, we systematically examined field excitatory postsynaptic potentials in stratum radiatum and population spikes in the adjacent stratum pyramidale of CA1 in wild-type mouse hippocampal slices. Soluble Aβ oligomers (oAβ) blocked hippocampal LTP and EPSP-spike (E-S) potentiation, and these effects were occluded by prior treatment with the glutamate uptake inhibitor TBOA. In accord, oAβ elevated glutamate levels in the hippocampal slice medium. Recording population spikes (PS) revealed that oAβ increased PS frequency and reduced LTP, and the latter effect was occluded by pretreatment with the GABA A antagonist picrotoxin. Whole-cell recordings showed that oAβ significantly increased spontaneous EPSC frequency. Decreasing neuronal activity by increasing GABA tone or partially blocking NMDAR activity prevented oAβ impairment of hippocampal LTP. Finally, treating slices with two antiepileptic drugs rescued the LTP inhibition induced by oAβ. We conclude that soluble Aβ oligomers at the low nanomolar levels present in AD brain increase neuronal excitability by disrupting glutamatergic/GABAergic balance, thereby impairing synaptic plasticity.
2012
Introduction: Alzheimer's disease (AD) is a common neurodegenerative disorder in elderly people with an impairment of cognitive decline and memory loss. β-amyloid (Aβ) as a potent neurotoxic peptide has a pivotal role in the pathogenesis of AD. This disease begins with impairment in synaptic functions before developing into later neurodegeneration and neuronal loss. The aim of this study was to evaluate the synaptic plasticity and electrophysiological function of granule cells in hippocampal dentate gyrus (DG) after intracerebroventricular (i.c.v.) administration of aggregated Aβ (1-42) peptide in vivo. Methods: Animals were divided to control and Aβ (1-42) groups. Long-term potentiation (LTP) in perforant path-DG synapses was assessed in order to investigate the effect of aggregated Aβ (1-42) on synaptic plasticity. Field excitatory post-synaptic potential (fEPSP) slope and population spike (PS) amplitude were measured. Results: Administration of Aβ (1-42) significantly decreased fEPSP slope and PS amplitude in Aβ (1-42) group comparing with the control group and had no effect on baseline activity of neurons. Conclusion: The present study indicates that administration of aggregated form of Aβ (1-42) into the lateral ventricle effectively inhibits LTP in granular cells of the DG in hippocampus in vivo.
Inhibitory Effects of Aβ-amyloid Aggregates on Synaptic Transmission in Hippocampal Neurons
Alzheimer's disease (AD) is characterized by a progressive brain neurodegeneration in which patients show significant cognitive impairments. Several pathological changes have been described in the postmortem brains of AD patients; the most common are amyloid plaques, neurofibrillary tangles, synaptotoxicity and neuronal death. Brain amyloid plaques are formed by the accumulation of -amyloid (Aβ) oligomers/aggregates, which are believed to trigger neurodegeneration. Cortical and hippocampal synapse densities are reduced early in the disease process, and the loss of these synapses correlates strongly with memory impairments. Therefore, it has been hypothesized that Aβ aggregates are responsible for the early synaptic disconnection and neuronal cell death observed in the later stages of this disorder. One of the consequences of Aβ aggregate interaction with neurons is an increase in intracellular calcium concentration that could, when large enough, create a critical alteration in normal ionic homeostasis. It has also been postulated that calcium influx occurs when Aβ aggregates induce the opening of calcium channels or the disruption of the plasmatic membrane. Here, we present new evidence supporting a direct interaction of Aβ aggregates with neuronal membrane components, which can strongly alter the functionality of central nervous system (CNS) synapses.
Scientific Reports, 2016
The oligomeric amyloid-β (Aβ) peptide is thought to contribute to the subtle amnesic changes in Alzheimer's disease (AD) by causing synaptic dysfunction. Here, we examined the time course of synaptic changes in mouse hippocampal neurons following exposure to Aβ 42 at picomolar concentrations, mimicking its physiological levels in the brain. We found opposite effects of the peptide with short exposures in the range of minutes enhancing synaptic plasticity, and longer exposures lasting several hours reducing it. The plasticity reduction was concomitant with an increase in the basal frequency of spontaneous neurotransmitter release, a higher basal number of functional presynaptic release sites, and a redistribution of synaptic proteins including the vesicle-associated proteins synapsin I, synaptophysin, and the post-synaptic glutamate receptor I. These synaptic alterations were mediated by cytoskeletal changes involving actin polymerization and p38 mitogen-activated protein kinase. These in vitro findings were confirmed in vivo with short hippocampal infusions of picomolar Aβ enhancing contextual memory and prolonged infusions impairing it. Our findings provide a model for initiation of synaptic dysfunction whereby exposure to physiologic levels of Aβ for a prolonged period of time causes microstructural changes at the synapse which result in increased transmitter release, failure of synaptic plasticity, and memory loss. Accumulation of amyloid-β (Aβ) and tau proteins in the brain are widely accepted as key pathogenetic events in Alzheimer's disease (AD) 1. Specifically, elevation of soluble oligomeric forms of Aβ preceding tau deposition has been viewed as a relevant early mechanism in disease etiopathogenesis. Nevertheless, amyloid-targeted therapies have so far failed to enter the market. As a consequence, the amyloid cascade hypothesis is increasingly disputed 2-5 , and various other pathogenetic mechanisms are acclaimed as potential targets for novel AD treatments 2-4,6-20. Despite these challenges to the role of Aβ in the disease etiopathogenesis, Aβ oligomers are clearly known to disrupt the cellular Ca 2+ homeostasis, to cause neuronal death, to contribute to oxidative stress, and to impair synaptic function as well as plasticity 21. Moreover, many in the field sustain that failure of the clinical trials against AD depended upon the fact that intervention occurred too late in the disease (i.e. after tau pathology has been triggered by Aβ) when it could no longer be stopped. Thus, a better understanding of the mechanisms starting Aβ toxicity in the brain might help establishing a therapy against AD.
Brain Research, 2009
Aβ42 oligomers as central in the etiology of the learning and memory deficits that are hallmarks of Alzheimer Disease. These effects are thought to occur by an interaction between Aβ42 and certain cellular effectors that induce LTP, however, the precise identity of the Aβ42-interactive signaling molecules is unknown. Identification of such effectors is made more difficult because LTP induced by different stimulation protocols can be expressed through heterogeneous signaling pathways. The aim of this study was to compare differences in the Aβ42-dependent levels of inhibition of LTPs that were induced using high frequency stimulation (HFS), versus theta burst stimulation (TBS). Our results show that untreated control brain slices tetanized with either HFS or TBS gave similar levels of LTP and post tetanic stimulation (PTP), suggesting that the response induced by either protocol was comparable. However, Aβ42 peptide significantly blocked LTP and PTP induced by HFS, but not when TBS was used. NMDA receptor antagonists, D-AP5 and ifenprodil, both blocked LTPs that were induced by HFS or TBS. We propose that unknown signaling effectors, other than the NMDA receptor, which are differentially involved in the induction of LTP by TBS, as compared to HFS, may be responsible for this resistance of TBS-induced LTP to Aβ42 dependent inhibition. (J.P. Smith). Abbreviations: AD, Alzheimer's Disease; Aβ42, amyloid beta 1-42; ACSF, artificial cerebral spinal fluid; fEPSP, field excitatory post synaptic potentiation; HFIP, hexafluoroisopropanol; HFS, high frequency stimulation; Hz, hertz; LTP, long term potentiation; PTP, post tetanic potentiation; s, second; sem, standard error of the mean; TBS, theta burst stimulation 0006-8993/$see front matter a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m w w w. e l s e v i e r. c o m / l o c a t e / b r a i n r e s
Biological Psychiatry, 2018
BACKGROUND: Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is a promising drug target for the treatment of Alzheimer's disease. Prolonged BACE1 inhibition interferes with structural and functional synaptic plasticity in mice, most likely by altering the metabolism of BACE1 substrates. Seizure protein 6 (SEZ6) is predominantly cleaved by BACE1, and Sez6 knockout mice share some phenotypes with BACE1 inhibitor-treated mice. We investigated whether SEZ6 is involved in BACE1 inhibition-induced structural and functional synaptic alterations. METHODS: The function of NB-360, a novel blood-brain barrier penetrant and orally available BACE1 inhibitor, was verified by immunoblotting. In vivo microscopy was applied to monitor the impact of long-term pharmacological BACE1 inhibition on dendritic spines in the cerebral cortex of constitutive and conditional Sez6 knockout mice. Finally, synaptic functions were characterized using electrophysiological field recordings in hippocampal slices. RESULTS: BACE1 enzymatic activity was strongly suppressed by NB-360. Prolonged NB-360 treatment caused a reversible spine density reduction in wild-type mice, but it did not affect Sez6-/mice. Knocking out Sez6 in a small subset of mature neurons also prevented the structural postsynaptic changes induced by BACE1 inhibition. Hippocampal long-term potentiation was decreased in both chronic BACE1 inhibitor-treated wild-type mice and vehicle-treated Sez6-/mice. However, chronic NB-360 treatment did not alter long-term potentiation in CA1 neurons of Sez6-/mice. CONCLUSIONS: Our results suggest that SEZ6 plays an important role in maintaining normal dendritic spine dynamics. Furthermore, SEZ6 is involved in BACE1 inhibition-induced structural and functional synaptic alterations.
Neural Plasticity, 2020
Recent evidence indicates that soluble amyloid-β (Aβ) species induce imbalances in excitatory and inhibitory transmission, resulting in neural network functional impairment and cognitive deficits during early stages of Alzheimer’s disease (AD). To evaluate the in vivo effects of two soluble Aβ species (Aβ25-35 and Aβ1-40) on commissural CA3-to-CA1 (cCA3-to-CA1) synaptic transmission and plasticity, and CA1 oscillatory activity, we used acute intrahippocampal microinjections in adult anaesthetized male Wistar rats. Soluble Aβ microinjection increased cCA3-to-CA1 synaptic variability without significant changes in synaptic efficiency. High-frequency CA3 stimulation was rendered inefficient by soluble Aβ intrahippocampal injection to induce long-term potentiation and to enhance synaptic variability in CA1, contrasting with what was observed in vehicle-injected subjects. Although soluble Aβ microinjection significantly increased the relative power of γ-band and ripple oscillations and s...