Trends in Neurosciences
ReviewTargeting small Aβ oligomers: the solution to an Alzheimer's disease conundrum?
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).
References (55)
- et al.
Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein
Biochem. Biophys. Res. Commun.
(1984) Aggregation state and neurotoxic properties of Alzheimer beta-amyloid peptide
Neurodegeneration
(1995)Methodological variables in the assessment of beta amyloid neurotoxicity
Neurobiol. Aging
(1992)Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease
Am. J. Pathol.
(1999)Amyloid beta-protein fibrillogenesis. Structure and biological activity of protofibrillar intermediates
J. Biol. Chem.
(1999)Aggregation of secreted amyloid β-protein into sodium dodecyl sulfate-stable oligomers in cell culture
J. Biol. Chem.
(1995)Enhanced production and oligomerization of the 42-residue amyloid β-protein by Chinese hamster ovary cells stably expressing mutant presenilins
J. Biol. Chem.
(1997)Clusterin (apoJ) alters the aggregation of amyloid beta-peptide (A beta 1-42) and forms slowly sedimenting A beta complexes that cause oxidative stress
Exp. Neurol.
(1995)- et al.
Postsynaptic protein phosphorylation and LTP
Trends Neurosci.
(2000) - et al.
Targeting learning
Trends Neurosci.
(1994)