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. 2011 Aug 26;6(1):63.
doi: 10.1186/1750-1326-6-63.

Alzheimer's disease: synapses gone cold

Robert M Koffie  1 , Bradley T Hyman, Tara L Spires-Jones
Affiliations

Alzheimer's disease: synapses gone cold

Robert M Koffie et al. Mol Neurodegener. .

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by insidious cognitive decline and memory dysfunction. Synapse loss is the best pathological correlate of cognitive decline in AD and mounting evidence suggests that AD is primarily a disease of synaptic dysfunction. Soluble oligomeric forms of amyloid beta (Aβ), the peptide that aggregates to form senile plaques in the brain of AD patients, have been shown to be toxic to neuronal synapses both in vitro and in vivo. Aβ oligomers inhibit long-term potentiation (LTP) and facilitate long-term depression (LTD), electrophysiological correlates of memory formation. Furthermore, oligomeric Aβ has also been shown to induce synapse loss and cognitive impairment in animals. The molecular underpinnings of these observations are now being elucidated, and may provide clear therapeutic targets for effectively treating the disease. Here, we review recent findings concerning AD pathogenesis with a particular focus on how Aβ impacts synapses.

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Figures

Figure 1
Figure 1
Molecular pathways of oligomeric Aβ mediated synaptic dysfunction. Oligomeric Aβ (oAβ) can induce calcium dyshomeostasis, trigger activation of caspase 3, or modulate the activity of NMDARs either directly or through intermediate molecules (shown as X) involved in the trafficking of NMDAR (e.g. EphB2). Activation of different subtypes of NMDA receptors may trigger different intrasynaptic pathways. Activation of NR2A containing NMDARs may lead to high changes in synaptic calcium concentration ([Ca2+]), which triggers downstream events involving CaMKII and pCREB (not shown), facilitating the induction of LTP, which promotes dendritic spine enlargement. Alternatively, activation of NR2B containing NMDAR may trigger a low rise in intrasynaptic calcium, which is favored by oAβ interactions with synapses (away from dotted line pathway), leading to calcineurin (CaN) activation; oAβ-dependent active caspase 3 can also activate CaN. Activated CaN dephosphorylates GluR subunits of AMPARs promoting internalization of AMPARs from the surface of synapses leading to LTD, which leads to dendritic spine shrinkage. Furthermore, active CaN dephosphorylates cofilin rendering it active to depolymerize dendritic spine actin, which leads to dendritic spine collapse and synapse loss.
Figure 2
Figure 2
Oligomeric Aβ associates with a subset of synapses in the brain of Alzheimer's disease transgenic mice. A) Array tomograms showing oligomeric Aβ (oAβ) localized to synaptic sites near senile plaques in APP/PS1 mice. B) A higher magnification view of the outlined square in panel A showing multiple pre- and post-synaptic elements colocalized with oAβ (arrows) stained with an oAβ specific antibody (NAB61). Scale bar is 10 μm in A and 2 μm in B.
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