. Amyloid beta from axons and dendrites reduces local spine number and plasticity. Nat Neurosci. 2010 Feb;13(2):190-6. PubMed.

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  1. This study by Wei et al. comes from one of the premier synapse biology labs. In brief, the study demonstrates that Aβ can be secreted from dendrites or axons in an activity-dependent mechanism that may also involve cholinergic signaling through nicotinic acetylcholine receptors (nAchRs). This secreted Aβ subsequently causes dendritic spine loss and depresses plasticity of spine morphology through an NMDA receptor-dependent mechanism. Proximity to the Aβ point source was a critical determinant in the magnitude of synapse loss, as spine loss was more pronounced within 10 μm of APP-expressing neurites. The use of two-photon time-lapse imaging of dendritic spines following a chemical plasticity protocol is a challenging technique, but provided a powerful morphologic correlate to the vast literature on the acute effects of Aβ on electrophysiology.

    This work also helps support recent studies on Aβ dynamics in the human brain. Specifically, increases in interstitial Aβ concentration in traumatic brain injury patients correlates with revival of neuronal activity (1). This finding confirmed an earlier observation in a mouse model that Aβ secretion coincides with neuronal activity (2). When produced, Aβ appears to perturb neural circuits manifested as an impaired default network activity on fMRI in the PIB-rich precuneus and posterior cingulate (3). As proposed by Wei et al., Aβ produced by activity-dependent mechanisms may likely be responsible for dysregulating synapse physiology. This pathologic role may become particularly important in states with high cortical soluble Aβ levels (4) or in the vicinity of plaques surrounded by a penumbra of Aβ oligomers (5). An unresolved and challenging question that remains after this study by Wei et al. is whether Aβ has a physiologic role. In an earlier study from this group, neuronal activity biased APP proteolysis towards β-secretase processing, and the resulting Aβ depressed excitatory synaptic transmission (6). It appears that this most recent study may also support a similar role for Aβ in homeostatic plasticity; however, focal hot spots of Aβ may overdrive a regulatory mechanism into the morphologic pathology seen in AD.

    References:

    . Amyloid-beta dynamics correlate with neurological status in the injured human brain. Science. 2008 Aug 29;321(5893):1221-4. PubMed.

    . Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron. 2005 Dec 22;48(6):913-22. PubMed.

    . Amyloid deposition is associated with impaired default network function in older persons without dementia. Neuron. 2009 Jul 30;63(2):178-88. PubMed.

    . A new amyloid beta variant favoring oligomerization in Alzheimer's-type dementia. Ann Neurol. 2008 Mar;63(3):377-87. PubMed.

    . Oligomeric amyloid beta associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):4012-7. PubMed.

    . APP processing and synaptic function. Neuron. 2003 Mar 27;37(6):925-37. PubMed.