ReviewSoluble oligomers of the amyloid β-protein impair synaptic plasticity and behavior☆
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
References (72)
- et al.
Nonlinear regulation of unitary synaptic signals by CaV(2.3) voltage-sensitive calcium channels located in dendritic spines
Neuron
(2007) - et al.
Alzheimer Amyloid beta-peptide inhibits the late phase of long-term potentiation through calcineurin-dependent mechanisms in the hippocampal dentate gyrus
Neurobiol Learn Mem
(2002) - et al.
Beta-amyloid(1-40) effects on behavior and memory
Brain Res
(1995) - et al.
Beta-amyloid deposition and other measures of neuropathology predict cognitive status in Alzheimer's disease
Neurobiol Aging
(1996) - et al.
A quantitative morphometric analysis of the neuronal and synaptic content of the frontal and temporal cortex in patients with Alzheimer's disease
J Neurol Sci
(1987) - et al.
Appearance of sodium dodecyl sulfate-stable amyloid beta-protein (Abeta) dimer in the cortex during aging
Am J Pathol
(1999) - et al.
Phenolic anti-inflammatory antioxidant reversal of Abeta-induced cognitive deficits and neuropathology
Neurobiol Aging
(2001) - et al.
Presence of sodium dodecyl sulfate-stable amyloid beta-protein dimers in the hippocampus CA1 not exhibiting neurofibrillary tangle formation
Am J Pathol
(1999) - et al.
Amyloid β protein (Aβ) in Alzheimer's disease brain
J Biol Chem
(1995) - et al.
Observation of metastable Aβ amyloid protofibrils by atomic force microscopy
Chem Biol
(1997)
AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss
Neuron
Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43)
Neuron
Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum?
Trends Neurosci
LTP and LTD: an embarrassment of riches
Neuron
Effects of an exogenous beta-amyloid peptide on retention for spatial learning
Behav Neural Biol
Bidirectional activity-dependent morphological plasticity in hippocampal neurons
Neuron
Delayed behavioral effects following intrahippocampal injection of aggregated A beta (1-42)
Brain Res
Aggregation of secreted amyloid β-protein into SDS-stable oligomers in cell culture
J Biol Chem
Morphology and toxicity of Aβ-(1-42) dimer derived from neuritic and vascular amyloid deposits of Alzheimer's disease
J Biol Chem
Dominant and differential deposition of distinct β-amyloid peptide species, AβN3(p3), in senile plaques
Neuron
The molecular pathology of Alzheimer's disease
Neuron
Intrahippocampal injections of exogenous beta-amyloid induce postdelay errors in an eight-arm radial maze
Neurobiol Learn Mem
Amyloid beta-protein fibrillogenesis. Structure and biological activity of protofibrillar intermediates
J Biol Chem
The profile of soluble amyloid b protein in cultured cell media. Detection and quantificaiton of amyloid β protein and variants by immunoprecipitation-mass spectrometry
J Biol Chem
Enhanced production and oligomerization of the 42-residue amyloid b-protein by Chinese hamster ovary cells stably expressing mutant presenilins
J Biol Chem
Shrinkage of dendritic spines associated with long-term depression of hippocampal synapses
Neuron
Amyloid β-protein (Aβ) assembly: Aβ 40 and Aβ 42 oligomerize through distinct pathways
Proc Natl Acad Sci USA
Preparation of aggregate-free, low molecular weight amyloid-beta for assembly and toxicity assays
Methods Mol Biol
Patterns of brain activation in people at risk for Alzheimer's disease
N Engl J Med
Generation of β-amyloid in the secretory pathway in neuronal and nonneuronal cells
Proc Natl Acad Sci USA
Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders
Annu Rev Neurosci
Natural oligomers of the amyloid β-protein specifically disrupt cognitive function
Nat Neurosci
Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer's disease model
Nat Neurosci
Dendritic spine changes associated with hippocampal long-term synaptic plasticity
Nature
Alzheimer's disease-affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss
Proc Natl Acad Sci USA
Amyloid β-peptide is produced by cultured cells during normal metabolism
Nature
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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.