Research ReportDifferent electrophysiological actions of 24- and 72-hour aggregated amyloid-beta oligomers on hippocampal field population spike in both anesthetized and awake rats
Research highlights
►Diffusible oligomeric assemblies of the amyloid β-protein (Aβ) could be the key pathogenic factor leading to Alzheimer's disease (AD). ►Different in vitro-aged and physico-chemically characterized Aβ(1–42) oligomer solutions differentially influenced population spike (pSpike) of the perforant pathway-evoked field potentials in the ventral hippocampal dentate gyrus in vivo. ►The 24-h Aβ oligomer solution increased the pSpike amplitude in both anesthetized and awake rats. ►The 72-h Aβ oligomer solution decreased the pSpike amplitude in both anesthetized and awake rats. ►The increased neuronal excitability after the 24-h Aβ oligomers could be related to the well-known comorbidity of AD and epilepsy
Introduction
According to the current view on the molecular pathological mechanisms of Alzheimer's disease (AD), the accumulation and aggregation of Aβ initiates a cascade of cellular changes that gradually leads to memory loss. It is known that amyloid monomers, produced from the amyloid precursor protein, form aggregates rich in β-sheet structure in a slow oligomerization process (DeMager et al., 2002, Nandi, 1996, Stine et al., 2003) and gradually form deposits in the limbic and association cortex of the brain of AD patients (Glenner et al., 1984, Masters et al., 1985). It has been shown in several studies that the small and soluble, non-fibrillar oligomers, rather than the large Aβ fibrils, are toxic (Cleary et al., 2005, Dahlgren et al., 2002, Haass and Selkoe, 2007, Kirkitadze et al., 2002, Klein et al., 2004, Lacor et al., 2004, McLean et al., 1999, Selkoe, 2002, Walsh et al., 2002, Walsh and Selkoe, 2004).
Aβ oligomers injected into the brain have been found to initiate various cytotoxic and immunological reactions, including axonal pathway distortion, dendritic arbor shrinkage, microglia activation, free radical release and inflammatory reactions (Walsh and Selkoe, 2004). Electrophysiologically it is well established, that Aβ oligomers decrease synaptic efficacy (Walsh and Selkoe, 2004, Walsh and Selkoe, 2007). The smallest synaptotoxic species to impair synapse structure and function are reported to be Aβ dimers (Mc Donald et al., 2010, Shankar et al., 2008).
Recently aberrant excitatory neuronal activity and nonconvulsive seizures were found in several different APP transgenic mouse lines (Minkeviciene et al., 2009, Palop et al., 2007). This highlighted the well-known clinical fact that there is a comorbidity of AD and epilepsy (Larner, 2010). Whether this comorbidity is just epiphenomenal, or there is a shared pathophysiology of seizures and AD, remains elusive (Larner, 2010, Minkeviciene et al., 2009).
Indeed there are conflicting data about how Aβ oligomers influence neuronal excitability. In an earlier whole cell recording study Aβ selectively augmented NMDA receptor-mediated synaptic currents (Wu et al., 1995a, Wu et al., 1995b), while later in a similar in vitro study, oligomeric Aβ decreased neuronal excitability (Yun et al., 2006). In an in vivo iontophoretic study, Aβ application irreversibly increased NMDA responses in the extracellular single-unit recordings (Molnar et al., 2004). Furthermore, as Aβ has a high affinity for the lipid component of the membrane (Verdier and Penke, 2004), it can interact with membrane proteins, including voltage operated calcium channels. However, the oligomerisation state of Aβ differentially affected the calcium channels (Innocent et al., 2010, Nimmrich et al., 2008, Ueda et al., 1997).
In this study therefore, to assess the importance of Aβ oligomerization, we measured the perforant path-evoked population potentials, to test the electrophysiological effect of different Aβ(1–42) oligomers on neuronal function. We injected in vitro-aged Aβ oligomer solutions with different aggregation times into the ventral hippocampal dentate gyrus of both anesthetized and awake freely moving rats. We observed a marked increase of the perforant path-evoked population action potentials (pSpike) after injection of the solution with 24 h aggregation time and a decrease of pSpike amplitude after injection of the 72-h solution. The same effects were observed in freely moving rats following injection of the 24-h and 72-h Aβ solutions. Thus, Aβ oligomers have opposite effects on neuronal excitability which depend on their degree of oligomerization.
Section snippets
Electrophysiological results
In anesthetized rats injected with 0-h Aβ(1–42) solution (1 μl of 200 μM Aβ), the hippocampal pSpike amplitude was unaltered (Fig. 1). The injection of 24-h Aβ aggregates increased, while 72-h Aβ aggregates decreased the pSpike amplitude, compared to the ACSF-treated animals at the same post-injection time (Fig. 1). The maximum effects were 161 ± 13% for the 24 h aggregates, and 60 ± 8% for the 72-h aggregates, measured 40 min after the end of the 30 min injection (Fig. 1).
In freely moving rats, the
Discussion
The present study reveals that Aβ solutions with aggregates in a different degree of oligomerization elicit opposite electrophysiological effects on pSpike amplitude in the hippocampal dentate gyrus, which depend on the aggregation time of the solution prior to the injection.
Inherent physiological effects have been previously demonstrated only for protofibrillar and fibrillar synthetic Aβ solutions: these included an increase in the number of excitatory postsynaptic currents (EPSCs) and also
Electrophysiological experiments
The care and treatment of all animals conformed to Council Directive 86/609/EEC, the Hungarian Act of Animal Care and Experimentation (1998, XXVIII), and local regulations for the care and use of animals in research. All efforts were taken to minimize the animals’ pain and suffering and to reduce the number of animals used.
Acute experiments were conducted on male Sprague-Dawley rats (n = 20) weighing ~ 250 g (n = 5 per group) from Charles River Laboratories Hungary, which were anesthetized by
Acknowledgments
This work was supported by the National Office for Research and Technology (NKTH, Hungary): DNT/RET, TÁMOP-4.2.2/08/1, CellKom/RET, and OTKA grants 68464, 81950. We thank Miklós Kellermayer and Ünige Murvay (Semmelweis University, Budapest) for their help in AFM. We thank Prof. Vincenzo Crunelli and Prof. Giuseppe Di Giovanni for critical reading of the manuscript.
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These authors contributed equally to this work.