Trends in Neurosciences
Volume 24, Issue 4, 1 April 2001, Pages 219-224
Journal home page for Trends in Neurosciences

Review
Targeting small Aβ oligomers: the solution to an Alzheimer's disease conundrum?

https://doi.org/10.1016/S0166-2236(00)01749-5Get rights and content

Abstract

Amyloid β (Aβ) is a small self-aggregating peptide produced at low levels by normal brain metabolism. In Alzheimer's disease (AD), self-aggregation of Aβ becomes rampant, manifested most strikingly as the amyloid fibrils of senile plaques. Because fibrils can kill neurons in culture, it has been argued that fibrils initiate the neurodegenerative cascades of AD. An emerging and different view, however, is that fibrils are not the only toxic form of Aβ, and perhaps not the neurotoxin that is most relevant to AD: small oligomers and protofibrils also have potent neurological activity. Immuno-neutralization of soluble Aβ-derived toxins might be the key to optimizing AD vaccines that are now on the horizon.

Section snippets

APP transgenic mice models for AD: CNS deficits without detectable amyloid

A huge clue for understanding Aβ-driven pathogenesis comes from transgenic mice models for AD in which transgenes for human APP (hu-APP) provide elevated brain levels of Aβ. As anticipated, multiple strains show specific AD-like neurological deficits. The surprise is that most of these deficits occur in the absence of amyloid deposits (for a summary, see http://pubweb.acns.nwu.edu/∼wklein/TiNS). These animal models thus recapitulate (in an exaggerated manner) the weak correlation between

Plaque-independent CNS pathology can be explained by the neurotoxicity of Aβ oligomers

Aβ monomers are innocuous and must self-associate to become neurotoxic, which until recently was taken to mean that Aβ must assemble into amyloid fibrils 5, 6. However, consistent with the transgenic mice story, recent data show that neurotoxicity can be fibril independent, but still dependent upon self-association.

One toxic form is the Aβ-derived protofibril (PF), first discovered as an intermediate in Aβ1–40-amyloidogenesis 16. By atomic force microscopy, PFs can be seen to be curvilinear

Oligomer-induced memory dysfunction before neuron death

Research focusing on the electrophysiological impact of Aβ oligomers suggests a new concept for early-stage AD. Declarative memory impairment occurs early in AD and typically is attributed to nerve cell death 25. An additional mechanism for memory loss is suggested by the rapid inhibition by ADDLs of LTP – a classical paradigm for synaptic plasticity and memory mechanisms 26. Complete inhibition takes place in less than 1 hr in vivo 24 and in culture (Fig. 3b). Unpotentiated population spikes,

Signal transduction

The kinetics and specificity of LTP inhibition suggest that ADDLs could target signal transduction. This possibility is untested for LTP, but knockout experiments have implicated an LTP-related protein tyrosine kinase, Fyn (29), in ADDL-induced neuron death 19. The role of Fyn in LTP is presumably downstream from glutamate receptors, to which it must be tethered by the scaffold protein PSD95 (30). Fyn signaling pathways also lead to upregulation of reactive oxygen species 31, known to be

A trend: soluble oligomers correlate better than fibrils with neurodegeneration

A crucial question that needs to be answered is whether nonfibrillar Aβ toxins exist in individuals with AD. Although we do not have the final answer, a shift in thinking is illustrated by a recent comment from Beyreuther and colleagues, who first characterized the APP gene: ‘Fibrillar Aβ has historically been viewed as the primary candidate for the neurotoxic element in Alzheimer's disease…[but recently we have] observed a clear correlation between the severity of the disease and what has been

What would be the target of an optimum Alzheimer's vaccine?

Antibodies designed to combat the CNS effects of Aβ are now in early-stage clinical trials 48. Immunization against Aβ neurotoxicity represents a major new approach to AD therapeutics and is based on the revolutionary findings of Schenk and colleagues 49. If immunization is established as a safe procedure, its optimum use will require knowledge of the therapeutic mechanism and the specific antigen(s) being targeted.

In Schenk's experiments, amyloid-producing transgenic mice were injected with

Acknowledgements

We are grateful to K. Viola (NWU) for extensive help in preparing the manuscript and expert assistance in computer graphics; to N. Patel (USC) for preparation of Fig. 2; to T. Morgan (USC), B. Chromy, M. Lambert (NWU), J. Rogers (Sun Health Research Institute) and Y. Ihara (University of Tokyo) for critical comments on portions of the text; to B.C. for preparation of the website; and to the NIA for support (W.L.K. and G.A.K., AG-15501; C.E.F., AG-13499).

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