Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior - PubMed (original) (raw)

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

Dennis J Selkoe. Behav Brain Res. 2008.

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 beta-protein (Abeta) 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 Abeta42 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 Abeta during some kinds of synaptic activity. Elevated levels of soluble Abeta42 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. Abeta 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 Abeta antibodies or small-molecule modulators of Abeta aggregation. This therapeutic progress has been accompanied by advances in imaging the Abeta deposits non-invasively in humans. A new diagnostic-therapeutic paradigm to successfully address AD and its harbinger, mild cognitive impairment-amnestic type, is emerging.

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Figure 1

Figure 1

Proposed pathways that regulate spine density and that are affected by Aβ oligomers, based on the results of our results. Ca2+ influx through synaptic NMDARs can activate at least two pathways that regulate spine density. On the left-hand side, high levels of Ca2+ accumulation, such as those reached during tetanic or suprathreshold synaptic stimulation, induce LTP via a CAMKII-dependent pathway (reviewed in [44]). LTP-inducing stimuli also trigger the enlargement of dendritic spines and growth of new spines in a NMDAR- and CAMKII-dependent manner [13, 26, 35, 37, 42]. Introduction of active CAMKII in neurons is sufficient to induce new spine growth [26]. In the right-hand side pathway, low levels of Ca2+ accumulation, such as those reached during low-frequency subthreshold stimulation, induce LTD through a calcineurin-dependent pathway (reviewed in [34]. LTD-inducing stimuli also lead to spine shrinkage via an NMDAR/calcineurin/cofilin-dependent pathway and spine retraction through an NMDAR-dependent pathway [42, 72]. The calcineurin and cofilin dependence of LTD-associated spine retraction have not been examined. In this model, full block of NMDARs interrupts both pathways, leading to no net spine loss. Partial block of NMDARs favors activation of the right-hand pathway, LTD induction, and loss of spines. In addition, multiple factors (A, B, C, and D) act independently of NMDARs, CAMKII, and calcineurin to regulate cofilin and spine density. We find that soluble Aβ oligomers decrease spine density in an NMDAR/calcineurin/cofilin-dependent manner, consistent with activation of the pathway shown on the right. Aβ oligomers reduce NMDAR-dependent Ca2+ transients, possibly shifting stimuli that normally activate the left-hand pathway to instead activate those on the right. This activation might occur through direct interaction of Aβ with NMDARs or by first activating unknown factors (X) that may lead to inhibition of NMDAR-mediated synaptic Ca2+ influx. Aβ may also facilitate NMDAR-dependent activation of calcineurin via additional pathways. Blue lines indicate levels at which soluble Aβ oligomers may modulate the pathway and red lines indicate elements of the pathway tested in this study.

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