Elsevier

Neurobiology of Aging

Volume 31, Issue 7, July 2010, Pages 1164-1172
Neurobiology of Aging

β-Amyloid-related peptides potentiate K+-evoked glutamate release from adult rat hippocampal slices

https://doi.org/10.1016/j.neurobiolaging.2008.08.009Get rights and content

Abstract

Accumulated evidence indicates that amyloid β (Aβ) peptides, by interacting with the central glutamatergic system, can lead to degeneration of neurons associated with Alzheimer’s disease (AD) pathology. However, very little is currently known about the role of peptides in the regulation of glutamatergic function in the normal brain. Given the evidence that peptides are produced constitutively in the normal brain, we investigated the possible association of amyloid precursor protein (APP)-containing neurons with the vesicular glutamatergic transporter-1 (VGluT1) and measured the effects of various Aβ peptides on endogenous glutamate release from adult rat brain slices. Our results showed that VGluT1 immunoreactivity is localized in close apposition to APP neurons, and that exogenous Aβ1–40, in a dose-dependent (10−12 to 10−7 M) manner potently increased K+-evoked glutamate release from hippocampal slices. This effect was observed with other Aβ peptides such as Aβ1–42, Aβ1–28 and Aβ25–35, but not with the reverse Aβ1–40 or Aβ25–35 sequences. Tetrodotoxin failed to alter the effects of Aβ1–40 on glutamate release, which suggests the lack of involvement of voltage-dependent Na+ channels. In addition to the hippocampus, Aβ1–40 was found to potentiate K+-evoked glutamate release from cortical slices, whereas in the striatum the effect did not reach significant levels. These results demonstrate that physiological concentrations of Aβ peptides can regulate the release of glutamate by acting on glutamatergic terminals. Additionally, the evidence that selected regions of the brain are sensitive to Aβ peptides suggests a potential link between the deposition of Aβ and the preferential vulnerability of brain regions observed in AD pathology.

Introduction

Excessive accumulation of amyloid β (Aβ) peptides is an invariable characteristic feature associated with the Alzheimer’s disease (AD) brain (Francis, 2003, Selkoe and Schenk, 2003). These peptides, which contain 39–42 amino acid residues, are generated from the amyloid precursor protein (APP) by successive cleavage mediated via the β-secretase and tetrameric γ-secretase complex (Clippingdale et al., 2001, Pereira et al., 2004). A number of earlier studies have indicated that Aβ peptides can be secreted constitutively and may have physiological functions in the normal brain (Selkoe and Schenk, 2003, Haass et al., 1992, Shoji et al., 1992). It is likely that an overproduction and/or lack of degradation may lead to amyloid aggregation as well as degeneration of neurons in selected regions of the AD brain. Of all the vulnerable regions, the pyramidal neurons of the neocortex, entorhinal cortex and hippocampus, which use glutamate as a neurotransmitter, are known to be affected early in the disease process (Butterfield and Pocernich, 2003, Cacabelos et al., 1999, Francis, 2003). Since overactivation of glutamatergic N-methyl-d-aspartate (NMDA) receptors can lead to both cognitive deficits and neuronal loss, it has been proposed that a sustained increase in extracellular glutamate levels (as a consequence of disrupted transporter function) and activation of the NMDA receptor may possibly be associated with the cognitive deficits and loss of neurons observed in AD brains (Hynd et al., 2004, Mattson, 2003, Michaelis, 1998, Waxman and Lynch, 2005). This is supported, in part, by the recent introduction of memantine, a non-competitive NMDA receptor antagonist that blocks glutamate neurotoxicity without interfering with its physiological action, for the treatment of AD patients (Cosman et al., 2007, Farlow, 2004, Robinson and Keating, 2006, Rogawski and Wenk, 2003, Wilcock, 2003). However, at present, neither the mechanisms by which Aβ-related peptides can cause AD pathology nor the role of these peptides in normal brain function are clearly established.

A number of studies over the last decade have provided evidence of a functional interrelationship between Aβ peptides and central glutamatergic neurons. This is supported by results showing that glutamate receptor activation by the agonist NMDA increases the production of Aβ peptide (Lesne et al., 2005), whereas Aβ peptide inhibits the uptake of glutamate and increases extracellular glutamate levels in neuronal as well as glial cultures (Fernandez-Tome et al., 2004, Harris et al., 1996, Noda et al., 1999). There is also evidence that Aβ-related peptides can enhance glutamate-induced toxicity, can promote NMDA receptor endocytosis, and can inhibit induction of long-term potentiation (LTP) in in vitro and in vivo paradigms (Gray and Patel, 1995, Itoh et al., 1999, Mattson et al., 1992, Snyder et al., 2005, Stephan et al., 2001, Walsh et al., 2002). These data, taken together, indicate that glutamatergic transmission can influence APP processing, whereas Aβ peptides can enhance extracellular glutamate levels and NMDA receptor-mediated neurotoxicity. Despite the critical relevance of these data, very little information is currently available on the significance of physiological concentrations of Aβ peptides in the regulation of glutamatergic function of the normal brain. The present study reports that nM concentrations of Aβ-related peptides, under acute conditions, can potentiate endogenous glutamate release from the adult rat hippocampus and cortex, the regions which are preferentially vulnerable in AD pathology.

Section snippets

Materials

Adult male Sprague–Dawley rats (2–3 months, 250–300 g) obtained from Charles River, St. Constant, Quebec, Canada, were used in the study. The animals were housed according to guidelines of the Canadian Council on Animal Care and University of Alberta Policies, and given food and water ad libidum. Various Aβ peptides, i.e., Aβ1–42, Aβ1–40, Aβ1–28, Aβ25–35, reverse sequence Aβ1–40 (i.e., Aβ40–1) and Aβ25–35 (i.e., Aβ35–25) were obtained from Bachem (Torrance, CA) and dl-threo-β-hydroxy aspartic

Localization of APP and VGluT1 in hippocampal formation

Our double immunofluroscence labeling reveals that APP immunoreactivity in the hippocampal formation, as reported earlier (Beeson et al., 1994, Ouimet et al., 1994), was evident primarily in CA1–CA3 pyramidal cell layer (Fig. 1A, D, and F), granule cells of the dentate gyrus and some of the polymorphic neurons of the hilus region. In contrast, immunoreactivity for VGluT1, which is known to be the main VGluT isoform expressed in the hippocampus (Herzog et al., 2006), was not observed in cell

Discussion

The present results indicate that Aβ-related peptides, under acute conditions, can potentiate K+-evoked glutamate release from selected regions of the adult rat brain. The effects of the peptide are concentration-dependent, TTX-insensitive and highly selective. Additionally, Aβ peptide was found to potentiate glutamate release from the hippocampus and frontal cortex but not significantly from striatum. These results, together with the evidence that APP neurons are evident in close proximity to

Disclosure statement

We would like to indicate that none of the authors included in this manuscript has had any actual or potential conflict of interest including financial, personal or other relationships with other people or organizations at any time that could inappropriately influence the work. Additionally, adult male rats used in the study were handled in accordance with protocols approved by the University of Alberta Policies on the handling and treatment of laboratory animals.

Acknowledgements

This work was supported by a grant from the Canadian Institutes of Health Research. SK is a recipient of Tier-II Canada Research Chair in Neurodegenerative Diseases and a Senior Scholar award from the Alberta Heritage Foundation for Medical Research. GB is a recipient of Tier-I Canada Research Chair in Neurochemistry and Drug Development.

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