Elsevier

Behavioural Brain Research

Volume 192, Issue 1, 1 September 2008, Pages 106-113
Behavioural Brain Research

Review
Soluble oligomers of the amyloid β-protein impair synaptic plasticity and behavior

https://doi.org/10.1016/j.bbr.2008.02.016Get rights and content

Abstract

During the last 25 years, neuropathological, biochemical, genetic, cell biological and even therapeutic studies in humans have all supported the hypothesis that the gradual cerebral accumulation of soluble and insoluble assemblies of the amyloid β-protein (Aβ) in limbic and association cortices triggers a cascade of biochemical and cellular alterations that produce the clinical phenotype of Alzheimer's disease (AD). The reasons for elevated cortical Aβ42 levels in most patients with typical, late-onset AD are unknown, but based on recent work, these could turn out to include augmented neuronal release of Aβ during some kinds of synaptic activity. Elevated levels of soluble Aβ42 monomers enable formation of soluble oligomers that can diffuse into synaptic clefts. We have identified certain APP-expressing cultured cell lines that form low-n oligomers intracellularly and release a portion of them into the medium. We find that these naturally secreted soluble oligomers – at picomolar concentrations – can disrupt hippocampal LTP in slices and in vivo and can also impair the memory of a complex learned behavior in rats. Aβ trimers appear to be more potent in disrupting LTP than are dimers. The cell-derived oligomers also decrease dendritic spine density in organotypic hippocampal slice cultures, and this decrease can be prevented by administration of Aβ antibodies or small-molecule modulators of Aβ aggregation. This therapeutic progress has been accompanied by advances in imaging the Aβ deposits non-invasively in humans. A new diagnostic–therapeutic paradigm to successfully address AD and its harbinger, mild cognitive impairment–amnestic type, is emerging.

Introduction

During most of the 20th century, neurodegenerative diseases remained among the most enigmatic disorders of medicine. The scientific study of these conditions was descriptive in nature, detailing the clinical and neuropathological phenotypes associated with various diseases, but etiologies and pathogenic mechanisms remained obscure. Beginning in the 1970s, advances in two principal areas – biochemical pathology and molecular genetics – combined to yield powerful clues to the molecular underpinnings of several previously “idiopathic” brain disorders. Among the classical neurodegenerative diseases, perhaps the most rapid progress occurred in research on Alzheimer's disease (AD). In disorders like Huntington's disease, amyotrophic lateral sclerosis and even Parkinson's disease, unbiased genetic screens, linkage analysis and positional cloning have identified causative genes that subsequently allowed the formulation of specific biochemical hypotheses. In sharp contrast, modern research on AD developed in the opposite order: the identification of the protein subunits of the classical brain lesions guided geneticists to disease-inducing genes, for example, APP, apolipoprotein E and tau. Thus, a biochemical hypothesis of disease – that AD is a progressive cerebral amyloidosis caused by the aggregation of the amyloid β-protein (Aβ) – preceded and enabled the discovery of etiologies.

As progress in deciphering genotype-to-phenotype relationships in AD accelerated during the last two decades, it became apparent that the key challenge for understanding and ultimately treating AD was to focus not on what was killing neurons over the course of the disease but rather on what was interfering subtly and intermittently with episodic declarative memory well before widespread neurodegeneration had occurred [53]. In other words, one wishes to understand the factors underlying early synaptic dysfunction in the hippocampus and then attempt to neutralize these as soon as feasible, perhaps even before a definitive diagnosis of AD can be made. This steady movement of the field toward ever-earlier stages of the disorder is exemplified by the recognition and intensive study of minimal cognitive impairment–amnestic type (MCI [46]). And yet patients who die with a diagnosis of MCI have been found to already have a histopathology essentially indistinguishable from classical AD [48]. Therefore, even earlier phases of this continuum are likely to become recognized, and these might show milder histopathology and might have biochemically, but not yet microscopically, detectable Aβ species that mediate synaptic dysfunction.

The IPSEN symposium for which this volume serves as a record focused on bringing together investigators at the forefront of elucidating the structure and function of hippocampal synapses with investigators focused on understanding how early assemblies of Aβ may compromise some of these synapses. This chapter will summarize some of the observations and discoveries made by the author and his colleagues over several years that have the goal of identifying the earliest synaptotoxic molecules in Alzheimer's disease—and neutralizing them.

Section snippets

Moving from synthetic Aβ peptides to naturally secreted Aβ assemblies

A wealth of data from many laboratories now supports the once controversial hypothesis that the accumulation and aggregation of Aβ initiates a complex cascade of molecular and cellular changes that gradually leads to the clinical features of MCI–amnestic type and then frank Alzheimer's disease [20], [21], [52]. As a result, understanding precisely how Aβ accumulation and assembly compromise synaptic structure and function has become the centerpiece of therapeutically oriented research on the

Naturally secreted Aβ oligomers abrogate hippocampal synaptic plasticity

In collaboration with the laboratory of Michael Rowan, we have taken advantage of our discovery that Chinese hamster ovary (CHO) cells stably expressing the AD-causing Val717Phe mutation in APP secrete soluble oligomers detectable on SDS gels as dimers, trimers and tetramers [47] to conduct a series of studies defining the electrophysiological activities of these assemblies. As mentioned above, we view these cell-derived, low-n oligomers as having several advantages over synthetic Aβ

Cell-derived oligomers interfere with the memory of a complex learned behavior

In collaboration with James Cleary and Karen Ashe at the University of Minnesota, we have been able to demonstrate significant cognitive deficits in a complex lever pressing task in adult rats that are directly attributable to a naturally secreted assembly form of Aβ [9]. The active Aβ species were the soluble oligomers, not monomers and in the absence of protofibrils and fibrils, and the oligomer effects were characterized by rapid onset, high potency and transience. These combined biochemical

Cell-derived oligomers decrease dendritic spine density in hippocampus by an NMDA-dependent signaling pathway

Our next approach to deciphering the synaptic effects of natural Aβ oligomers was to ask whether they can induce structural alterations of synapses in association with the clear functional deficits described in the previous two sections above. We exposed organotypic rat hippocampal slice cultures that had been biolistically transfected with EGFP to sub-nanomolar concentrations of SEC-separated 7PA2 cell Aβ monomers or dimers/trimers for periods varying from 1 to 15 days. We observed a marked

Conclusions

Through a series of systematic studies of soluble oligomers of human Aβ secreted by cultured cells, we have documented that low-n oligomers – but not monomers from the same source and at higher concentrations – can inhibit LTP without affecting basal synaptic transmission, can reversibly alter the structure of excitatory synapses by decreasing spines, and can interfere with the memory of a learned behavior in healthy adult rats. We interpret these data to signify that small diffusible oligomers

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    This article has also been published in D.J. Selkoe and Y. Christen (eds.), Synaptic plasticity and the mechanism of Alzheimer's disease, Heidelberg, Springer Verlag, 2008. It is published in the special issue of Behavioural Brain Research with Springer's permission.

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