Elsevier

Neurobiology of Aging

Volume 30, Issue 10, October 2009, Pages 1608-1613
Neurobiology of Aging

Inhibition of LTP by beta-amyloid is prevented by activation of β2 adrenoceptors and stimulation of the cAMP/PKA signalling pathway

https://doi.org/10.1016/j.neurobiolaging.2007.12.004Get rights and content

Abstract

Beta-amyloid (Aβ) is the main component of the extracellular plaques present in patients with Alzheimer's disease (AD) and studies have shown that exogenous application of Aβ results in neurodegeneration. As a model of the neurodegenerative action of Aβ, we have previously shown that acutely applied Aβ inhibits the induction of LTP in the hippocampus in vitro. In the present studies, we have studied the effect of β-adrenoceptor activation on the Aβ inhibition of LTP. Pharmacological activation of β2 adrenoceptors, but not of β1 adrenoceptors, was found to prevent the Aβ evoked inhibition of LTP in the dentate gyrus of adult animals. The prevention of the effect of Aβ was shown to occur via the cAMP/PKA signaling pathway as the adenylate cyclase-stimulating agent forskolin prevented the Aβ inhibition of LTP, an action prevented by the PKA inhibitor, Rp-8-Br-cAMPs. We suggest microglia as a likely site of action of the neuroprotective effect of β2 adrenoceptor activation. Therapeutic treatment for AD may include agents that activate β2 receptors and elevate cAMP.

Introduction

Alzheimer's disease (AD) is characterised by the presence of senile plaques composed of deposits of Aβ, a cleavage product of beta-amyloid precursor protein (APP). Aβ has been strongly implicated as a causal factor in AD, and there is evidence that Aβ-induced dysfunction of synaptic plasticity contributes to the early memory loss that preceeds neuronal degeneration (Small et al., 2002). Synthetic and cell-derived naturally secreted human Aβ have been shown to inhibit long-term potentiation (LTP) in the hippocampus, both in our laboratory in vivo (Cullen et al., 1997, Walsh et al., 2002) and in vitro (Wang et al., 2004a), and in other laboratories (Lambert et al., 1998, Vitolo et al., 2002). The block of LTP by Aβ may be involved in the memory deficit observed in the early stages of AD.

A chronic inflammatory reaction driven by microglial activation occurs at an early stage of AD (Griffin et al., 1998, Akiyama et al., 2000). Moreover, abundant reactive microglia surround beta-amyloid plaques in the AD brain (McGeer and McGeer, 1995, Cotman and Su, 1996), and treatment with anti-inflammatory agents correlates with a large reduction in plaque-associated reactive microglia and a decrease in severity of AD (MacKenzie and Munoz, 1998). In addition, Aβ causes activation of microglia cells in culture (Tan et al., 1999, Akiyama et al., 2000, Combs et al., 2000, Bamberger et al., 2003), and activated microglial cells have been shown to be the link between Aβ deposition and neuronal death (Eikelenboom et al., 1994, McGeer and McGeer, 1995). We have recently shown that activation of microglia, followed by activation of free radicals, inflammatory agents and stress kinases including the cytokine tumor necrosis factor, the reactive nitrogen and oxygen species nitric oxide and superoxide, and also stress kinases including p38 MAP kinase and c-Jun N-terminal kinase (JNK), are all essential for the Aβ inhibition of LTP (Wang et al., 2004b, Wang et al., 2005).

In addition to its role as a classical neurotransmitter, noradrenaline (NA) functions as an endogenous anti-inflammatory agent (Feinstein et al., 2002, Dello Rosso et al., 2004), and is known to inhibit expression of tumor necrosis factor (TNF) (Hu et al., 1991), interleukin-1β (Willis and Nisen, 1995) and nitric oxide synthase (Feinstein, 1998). Neuroinflammation is a major contribution to AD (Griffin et al., 1998, Akiyama et al., 2000), and may be caused in part by a reduction of NA action, as degeneration of neurons in the locus coeruleus (LC) and reduced levels of NA are known to occur in AD. In addition, decreased numbers of LC neurons significantly correlated with Aβ plaques and the severity of dementia in AD (Bondareff et al., 1987) and LC neuronal degeneration in an animal model of AD increased beta-amyloid plaque burden (Kalinin et al., 2007). The anti-inflammatory effect of NA is likely to be exerted via its effect on microglia. Thus NA depletion results in increased microglial cytokine expression (Heneka et al., 2002), and noradrenergic axon terminals are found in close contact to microglia (German et al., 1992).

In the present study, we have investigated the role of β-adrenoceptors and the downstream cAMP/PKA signalling pathway on the Aβ inhibition of LTP. We show that activation of β2 adrenoceptors, but not β1 adrenoceptors, and the PKA pathway prevents the Aβ inhibition of LTP, and suggest that therapeutic treatment for AD may include agents that activate β2 receptors and elevate cAMP.

Section snippets

Preparation of slices

All experiments were carried out on transverse slices of the rat hippocampus (males, age 3–4 weeks, weight 40–80 g). The brains were rapidly removed after decapitation and placed in cold oxygenated (95% O2/5% CO2) media. Slices were cut at a thickness of 350 μm using an Intracell Plus 1000 and placed in a storage container containing oxygenated medium at room temperature (20–22 °C) for 1 h. The slices were then transferred to a recording chamber for submerged slices and continuously superfused at a

Aβ inhibits induction of LTP

LTP was induced by brief HFS in the medial perforant path of the dentate gyrus in young adult animals except were indicated. The induction of LTP by a brief HFS in the dentate gyrus was prevented by pre-perfusion of Aβ (500 nM) for 40 min prior to HFS, confirming previous studies (Wang et al., 2004a, Wang et al., 2004b, Wang et al., 2005). Thus LTP in the presence of Aβ (500 nM), a concentration previously found to cause maximum inhibition of LTP (Wang et al., 2004a), measured 103 ± 4%, n = 5, at 1 h

Discussion

We have shown in the present studies that activation of β-adrenoceptors prevents Aβ-mediated inhibition of LTP. There is considerable previous evidence for the importance of an anti-inflammatory effect of NA in preventing AD. Thus NA depletion potentiates Aβ-induced inflammation in the rodent cortex (Heneka et al., 2002), and NA deficiency increased Aβ plaque deposition in a rodent model of AD (Kalinin et al., 2007). Moreover, recent studies have shown that NA protects neurons from

Acknowledgements

The project was supported by the Science Foundation, Ireland and by the National Nature Science Foundation of China, Ningbo. The approval of the BioResources Unit, Trinity College, Dublin, Ireland, was granted for use of the animals in this study.

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