Neurotoxicity of amyloid β-protein: synaptic and network dysfunction

Abstract

Evidence for an ever-expanding variety of molecular mediators of amyloid β-protein neurotoxicity (membrane lipids, receptor proteins, channel proteins, second messengers and related signaling cascades, cytoskeletal proteins, inflammatory mediators, etc.) has led to the notion that the binding of hydrophobic Aβ assemblies to cellular membranes triggers multiple effects affecting diverse pathways. It appears unlikely that there are only one or two cognate receptors for neurotoxic forms of Aβ and also that there are just one or two assembly forms of the peptide that induce neuronal dysfunction. Rather, various soluble (diffusible) oligomers of Aβ that may be in dynamic equilibrium with insoluble, fibrillar deposits (amyloid plaques) and that can bind to different components of neuronal and non-neuronal plasma membranes appear to induce complex patterns of synaptic dysfunction and network disorganization that underlie the intermittent but gradually progressive cognitive manifestations of the clinical disorder. Modern analyses of this problem utilize electrophysiology coupled with synaptic biochemistry and behavioral phenotyping of animal models to elucidate the affected circuits and assess the effects of potential therapeutic interventions.

Figure 1.

Presynaptic and postsynaptic regulation of synaptic transmission by amyloid β-protein (Aβ). (A) Hypothetical relationship between Aβ level and synaptic activity. Intermediate levels of Aβ enhance synaptic activity presynaptically, whereas abnormally high or low levels of Aβ impair synaptic activity by inducing postsynaptic depression or reducing presynaptic efficacy, respectively. (B) Within a physiological range, small increases in Aβ primarily facilitate presynaptic functions, resulting in synaptic potentiation. (C) At abnormally high levels, Aβ enhances long-term depression (LTD)-related mechanisms, resulting in postsynaptic depression and loss of dendritic spines (modified from Palop and Mucke 2010).

Figure 2.

Schematic of the principal pathways implicated by this study in conventional LTD and in LTD facilitated by soluble Aβ oligomers (left panel). Conventional LTD requires NMDAR-mediated influx of extracellular calcium and liberation of intracellular calcium stores. This ultimately activates PP2B, GSK-3b, or p38 MAPK signaling pathways that induce LTD. (Right panel) Soluble Aβ oligomers lead to activation of more NMDAR, leading to extracellular calcium influx and activation of PP2B and GSK-3b pathways to facilitate LTD. Our data suggest that Aβ oligomers decrease glutamate uptake by neuronal transporters (red ×’s), resulting in the enhanced activation of NMDARs and thus facilitation of LTD-inducing pathways.

Figure 3.

Pathologically elevated Aβ elicits abnormal patterns of neuronal activity in circuits and in wider networks in Alzheimer disease–related mouse models. (A) Neuronal circuits are formed by synaptic interactions between excitatory and inhibitory cells. Aβ might differentially affect excitatory (+) and inhibitory (−) synapses and cells, producing complex imbalances in circuit and network activity. (B) At the network level, high levels of Aβ increase network synchrony and elicit epileptiform activity, as illustrated here in EEG recordings from the left and right parietal cortex (LPC and RPC, respectively) of nontransgenic (NTG) controls (blue) and hAPP transgenic mice from line J20 (red). (C) hAPP mice show fluctuations in the neuronal expression of synaptic activity–dependent genes, suggesting network instability. Top: Compared with NTG controls (left), hAPP-J20 mice show abnormally low (middle) or high (right) Arc expression in granule cells of the dentate gyrus (adapted, with permission, from Palop et al. 2005, 2007). Percentages indicate the proportion of mice showing the different patterns of Arc expression. Such marked increases in Arc expression are typically caused by seizure activity. Bottom: Interpretive diagram. Marked fluctuations in neuronal activity may directly impair cognition by reducing the time the network spends in activity patterns that promote normal cognitive functions. (D) In cortical circuits of mice monitored in vivo by calcium imaging, most neurons in NTG controls (blue traces) have an intermediate level of activity, whereas many neurons in hAPP/PS1 transgenic mice with high Aβ levels (red traces) are either hypoactive (top) or hyperactive (bottom). (Adapted, with permission, from Palop and Mucke 2010.)