Elsevier

Brain Research

Volume 924, Issue 2, 11 January 2002, Pages 133-140
Brain Research

Research report
Soluble oligomers of β amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus

https://doi.org/10.1016/S0006-8993(01)03058-XGet rights and content

Abstract

The dementia in Alzheimer disease (AD) is usually attributed to widespread neuronal loss in conjunction with the pathologic hallmarks of intracellular neurofibrillary tangles and extracellular plaques containing amyloid (Aβ) in fibrillar form. Recently it has been demonstrated that non-fibrillar assemblies of possess electrophysiologic activity, with the corollary that they may produce dementia by disrupting neuronal signaling prior to cell death. We therefore examined the effects of soluble oligomers of Aβ1-42 on long-term potentiation (LTP) and long-term depression (LTD), two cellular models of memory, in the dentate gyrus of rat hippocampal slices. Compared with vehicle controls, slices pre-incubated 60 min in the presence of Aβ-derived diffusible ligands (ADDLs) showed no differences in threshold intensity to evoke a synaptic response, slope of field excitatory post-synaptic potentials (EPSPs), or the input/output function. Tetanus-induced LTP and reversal of LTD were strongly inhibited in ADDLs-treated slices whereas LTD was unaffected. These data suggest that soluble non-fibrillar amyloid may contribute to the pathogenesis of AD both by impairing LTP/memory formation at the cellular level and by creating ‘neuroplasticity imbalance’ manifested by unopposed LTD in the setting of impaired capacity for neural repair via reversal of LTD or LTP.

Introduction

Requisite features in the neuropathologic diagnosis of Alzheimer disease (AD) include neuritic plaques composed of amyloid beta protein (Aβ) in fibrillar form, neuronal dystrophy with intracytoplasmic neurofibrillary tangles, and widespread neuronal loss [1]. The proximity of Aβ fibrils to dystrophic neurites and reactive glia in mature plaques in post mortem tissue, as well as the correlation of in vitro toxicity of Aβ with its aggregation state, have led to the assumption that fibril accumulation per se underlies neuronal degeneration in AD. Dementia, in turn, has been attributed to neuronal loss and cerebral atrophy.

Recently these assumptions have been challenged in two important ways. One is the recognition that other Aβ derivatives, such as protofibrils (intermediates in the process of fibrillogenesis [19], [20], [43]) or oligomers formed independent of or in the absence of fibril formation [28], have neurotoxic potential. The second is the hypothesis that memory loss in AD may result from synaptic dysfunction or neuronal signaling abnormalities that precede massive neuronal degeneration [8], [9], [13], [21], [28], [40]. Long-term potentiation (LTP) and long-term depression (LTD) are complementary cellular models of learning and memory that constitute an attractive means of detecting perturbations of synaptic functioning in the absence of overt neuronal death. We have recently demonstrated that small diffusible oligomers of Aβ1-42 (referred to as ADDLs for Aβ-derived diffusible ligands) cause death of hippocampal pyramidal and granule cells at low concentrations in organotypic central nervous system cultures after 24-h incubation [28]. In the present study we report the effects of ADDLs on basic neurotransmission, short-term plasticity, LTP, and LTD. We found that ADDLs differentially affect the latter opposing forms of long-term plasticity by strongly inhibiting tetanically-induced potentiation at both naive and previously depressed synapses but completely sparing low-frequency induced long-term depression.

Section snippets

Animal age and slice preparation

Synaptic LTP (measured in field excitatory post synaptic potentials, EPSPs) is inconsistently elicited at the medial perforant path-granule cell synapse in dentate gyrus of rats ≤19 days old, but consistently demonstrated in animals over 20 days old [41], [42]. In contrast, LTD is considerably more robust in younger animals. To maximize our ability to detect amyloid β effects on synaptic plasticity, we therefore used 20–30-day-old rats in experiments involving LTP but substituted 14–19-day-old

Basic synaptic function and short-term plasticity

To distinguish ADDLs effects on long-term plasticity from effects on neurotransmission we examined several aspects of basic synaptic function and short-term plasticity.

We examined the effects of ADDLs on overall slice excitability by comparing threshold current intensities and the slope and amplitude distributions of EPSPs evoked in slices pre-incubated in ADDLs versus vehicle-pre-incubated slices. At a fixed pulse width of 50 μs, the threshold current required to evoke an EPSP did not differ

Discussion

In this study we examined the effects of soluble oligomers of Aβ1-42 (ADDLs) on neurotransmission and plasticity at the medial perforant path-granule cell synapse in hippocampal dentate gyrus in vitro. Our major finding is that brief (60 min) pre-incubation in nanomolar concentrations of ADDLs strongly inhibits both synaptic LTP and the reversal of LTD when these are induced by tetanic stimulation, but does not affect the induction of LTD by low frequency stimulation.

Acknowledgements

This work was supported in part by NIA AG15501, the Boothroyd Foundation and an anonymous bequest to W.L.K.; contributions from The Crown Family, The Ruggles Neurology Research Fund, and an Evanston Northwestern Healthcare Auxiliary Research Scholar Award to B.L.T.; and contributions from Open Hearts for Retarded Children to J.F.P. We thank Drs MaryJo LaDu, Gui-lan Ye, Nelson Spruston, and Klara Olofsdotter for helpful discussion and critical comments on the manuscript, and Dr Steven Zecker for

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