Aβ toxicity in Alzheimer’s disease: globular oligomers (ADDLs) as new vaccine and drug targets

doi:10.1016/S0197-0186(02)00050-5

Neurochemistry International

Volume 41, Issue 5, November 2002, Pages 345-352

https://doi.org/10.1016/S0197-0186(02)00050-5 Get rights and content

Abstract

Over the past several years, experiments with synthetic amyloid-beta peptide (Aβ) and animal models have strongly suggested that pathogenesis of Alzheimer’s disease (AD) involves soluble assemblies of Aβ peptides (Trends Neurosci. 24 (2001) 219). These soluble neurotoxins (known as ADDLs and protofibrils) seem likely to account for the imperfect correlation between insoluble fibrillar amyloid deposits and AD progression. Recent experiments have detected the presence of ADDLs in AD-afflicted brain tissue and in transgenic-mice models of AD. The presence of high affinity ADDL binding proteins in hippocampus and frontal cortex but not cerebellum parallels the regional specificity of AD pathology and suggests involvement of a toxin receptor-mediated mechanism. The properties of ADDLs and their presence in AD-afflicted brain are consistent with their putative role even in the earliest stages of AD, including forms of mild cognitive impairment.

Introduction

No one knows for certain what causes Alzheimer’s disease (AD). Many factors are involved, including inflammation, oxidative damage, and cytoskeletal abnormalities. The dominant hypothesis of the past 10 years, however, has been the “amyloid cascade” (Klein, 2000). In this hypothesis, dementia in AD depends on neuron death caused by amyloid fibrils; these fibrils, which are found in senile plaques, are large insoluble polymers generated from the 42 amino-acid, self-aggregating amyloid-beta peptide (Aβ).

The amyloid cascade hypothesis, despite its many strengths, has significant flaws, and it has not been fully accepted. This article reviews recent evidence that fibrillar amyloid is not the only toxic form of Aβ, perhaps not even the most relevant form. Evidence now points to a pathogenic role for small toxins that comprise globular Aβ oligomers (Klein et al., 2001). These soluble oligomers, which have been called “ADDLs,” present novel opportunities to develop AD vaccines and therapeutic drugs.

This article will discuss five issues: (i) the ADDL hypothesis, and how it solves the major problem with the amyloid cascade hypothesis; (ii) the experimental basis for the ADDL hypothesis, from toxin structure to experimental nerve cell biology; (iii) preliminary attempts at validation, comprising recent efforts to measure and characterize ADDLs in AD patients and in transgenic-mice models of AD; (iv) the mechanism of toxicity, with links to particular signal transduction pathways and toxin receptors; (v) use of ADDLs for development of therapeutic drugs and AD vaccines.

Section snippets

The ADDL hypothesis: missing links in Aβ toxicity

Over the past 10 years, there has been a profound interest in the possibility that toxins made from the small Aβ cause neuronal dysfunction and death in AD. In the early 1990s, two landmark findings from experimental nerve cell biology provided a direct link between Aβ and neurodegeneration. First, Yankner and Cotman and their groups at Harvard and UC-Irvine showed that solutions containing synthetic Aβ peptide can be toxic to CNS neurons (Busciglio et al., 1992, Pike et al., 1993). Second,

Experimental origin of the ADDL hypothesis

The first indication that Aβ neurotoxicity might not require large fibrillar aggregates came from studies by Caleb Finch’s group at University of Southern California (Oda et al., 1994, Oda et al., 1995). They found that a glia-secreted protein called ApoJ blocks formation of large Aβ aggregates. This appears to be a chaperone-like activity, as inhibition requires only 5% molar amounts of ApoJ relative to Aβ. Most importantly, blocking formation of sedimentable aggregates does not block

Validation: are ADDLs the missing links in AD pathogenesis?

An important question now under study is whether ADDLs, which form readily in vitro, actually accumulate in brains of APP-transgenic-mice and AD patients. Detection of endogenous ADDLs would provide strong prima facie evidence for the ADDL hypothesis.

As mentioned, analyses of aqueous extracts from brains of TG mice models and AD autopsies suggest a correlation between synapse loss and the levels of soluble amyloid peptides. Correlations in these ELISA studies were imprecise, however, probably

Mechanism: toxin receptors and signal transduction

ADDLs are neurotoxic molecules that accumulate in AD brains. It clearly is important, therefore, to establish the molecular basis for their toxicity. Our current model is that ADDLs cause neuronal dysfunction and degeneration by specific disruption of neuronal signal transduction (Klein, 2000). We propose that these specific signaling effects depend on interaction between ADDLs and differentially-expressed toxin receptors.

The specificity implied by the model is consistent with the differential

Use of ADDLs in vaccines and drug development

Great interest is now focused on vaccine development as a therapeutic approach to AD thanks to the pioneering work of Dale Schenk and his colleagues at Elan Pharmaceuticals (Schenk et al., 1999). Schenk’s group found that vaccinating transgenic APP-mice with typical fibrillar preparations of Aβ (which are mixtures of large fibrillar aggregates, protofibrils, ADDLs, and monomers) can reduce plaque-burden and help maintain healthy neurite structure.

We have begun to investigate the possibility

Acknowledgements

This article is based on a lecture presented at the ISN satellite conference “Cell communication in the nervous system: function and dysfunction.” The author would like to thank the organizers of the meeting, Drs. Marco Prado and Fernando de Mello for their efforts in creating a most successful and stimulating symposium. He also is grateful for support from the National Institutes of Health, from the Boothroyd, Feiger and French Foundations, from benefactors of Northwestern University, and from

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Aβ toxicity in Alzheimer’s disease: globular oligomers (ADDLs) as new vaccine and drug targets

Abstract

Introduction

Section snippets

The ADDL hypothesis: missing links in Aβ toxicity

Experimental origin of the ADDL hypothesis

Validation: are ADDLs the missing links in AD pathogenesis?

Mechanism: toxin receptors and signal transduction

Use of ADDLs in vaccines and drug development

Acknowledgements

J. Biol. Chem.

Neurobiol. Aging

Trends Neurosci.

Neuron

Am. J. Pathol.

Biochem. Biophys. Res. Commun.

Exp. Neurol.

J. Biol. Chem.

J. Biol. Chem.

Brain Res.

J. Physiol Paris

Neurosci. Lett.

Nonfibrillar Aβ toxins in AD: an immunoassay to characterize ADDL formation and identify ADDL-blocker compounds

Soc. Neurosci. Abs.

Wnt signaling function in Alzheimer’s disease

Brain Res. Brain Res. Rev.

Nonfibrillar Aβ toxins in Alzheimer’s pathogenesis: presence of ADDLs and ADDL-binding proteins in Alzheimer’s disease brains

Soc. for Neurosci. Abs.

Protofibrillar intermediates of amyloid-beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons

J. Neurosci.