Numerous studies indicate that Aβ peptides are important for initiating the pathogenesis of Alzheimer’s disease2
. The mechanisms by which this occurs are not known, although recent studies have indicated that Aβ can reduce synaptic transmission and lead to the loss of synapses4,5,16
. Although Aβ is produced in vesicles from the secretory and endosomal system (reviewed in ref. 41
), it has not been clear whether the Aβ that produces synaptic deficits originates from pre- or postsynaptic compartments. Previous studies found that APP can be transported anterogradely in axons32,33,35
and that Aβ can be made in axonal terminal fields29
; however, these studies did not demonstrate synaptic defects from axonally released Aβ. Other studies have shown that surgical lesions of axons decreased Aβ-rich plaques in axonal terminal regions of APP transgenic animals31,42
. However, these ablations should also reduce postsynaptic depolarization, which could reduce dendritic Aβ. Indeed, some studies have shown that overexpression of APP in dendritic compartments can reduce synaptic transmission in nearby neurons that do not overexpress APP, suggesting that dendritic Aβ can affect nearby synapses13
We found that overexpression of APP in either dendritic or axonal compartments led to a reduction in spine density and plasticity in nearby neurons. This effect is relevant to Alzheimer’s disease, as Aβ application at levels reached in the brains of individuals with Alzheimer’s disease36
produced a similar reduction in spine density and plasticity5
that could similarly be prevented by AP5. This effect was likely a result of secreted Aβ, as blockade of Aβ secretion by a γ-secretase inhibitor blocked spine reduction and impaired plasticity by APP overexpression. Furthermore, expression of APP(MV), a mutant form of APP that does not produce Aβ, but makes other cleavage products of APP, failed to produce a reduction in spine density4
. It is possible that production of Aβ in axons or dendrites leads to secretion of additional toxic substances or prevents normal synaptic function and thereby leads to the local effects that we observed. Identifying the local target of Aβ that leads to reduction of spines and their plasticity would help to elucidate the mediators of these synaptic effects. Our findings indicate that Aβ from axonal or dendritic compartments can lead to a loss of synaptic structure and function. However, we employed acute production or delivery of Aβ. Thus, the effects that we observed may not be entirely representative of events that occur in a chronic condition such as Alzheimer’s disease. Nevertheless, the effects that we observed in spine reduction were similar in magnitude and in pharmacological sensitivity to effects produced by concentrations of Aβ that are estimated to be present in the brains of individuals with Alzheimer’s disease36,43
. Our results do not provide information regarding the source of Aβ in nonpathological conditions, where lower levels are likely produced. It is noteworthy that in Alzheimer’s disease regions in the brain that are synaptically connected (for example, entorhinal cortex and hippocampus) can be affected in temporally linked manner. Our findings suggest that neurons in entorhinal cortex with increased Aβ production would affect the entorhinal cortex through its Aβ-rich dendrites and the dentate gyrus through its Aβ-rich axons.
Blockade of nAChRs with α-bungarotoxin led to a reduction of Aβ secretion from APP-overexpressing neurons. α7-containing nAChRs are present at synaptic and extrasynaptic sites on pre- and postsynaptic compartments, as well as in the cell bodies of hippocampal pyramidal neurons44,45
. However, organotypic hippocampal slices have few or no cholinergic neurons. Therefore, there is probably a ligand other than acetylcholine acting on nAChRs that is blocked by α-bungarotoxin. One possibility is that Aβ acts on nAChRs46
that are close to the site of Aβ release, leading to increased intracellular calcium47
, which leads to an increase in Aβ production and/or secretion. That is, Aβ could be part of a positive feedback loop that is mediated by nAChR activation and leads to increased Aβ secretion. Blockade of nAChRs would decrease Aβ secretion and reduce the effects of APP overexpression on spine density and plasticity. Additional protective mechanisms by which α-bungarotoxin acts cannot be ruled out. It is notable that a widely used treatment strategy for Alzheimer’s disease is to increase brain acetylcholine levels (reviewed in ref. 48
). Our results suggest that this may lead to increase Aβ secretion and would therefore be detrimental. Indeed the long-term effect of enhancing acetylcholine levels on Alzheimer’s disease progress is still in question48
Blockade of NMDA receptors produced effects different from blockade of nAChRs. AP5 did not reduce the secretion of Aβ. However, AP5 did prevent spine loss in cells overexpressing APP, on nearby cells and in slices exposed to exogenous Aβ. Thus, NMDA receptor activation is required for Aβ to exert its effects on spines, consistent with recent results5
. It is noteworthy that the protective effects of AP5 or a γ-secretase inhibitor on spine plasticity in cells overexpressing APP could be seen with only 1 h pretreatment of slices with the drug. Apparently, the effects of Aβ during this period are important for its effects on plasticity and they require NMDA receptor activity. This effect is reminiscent of findings that mild activation of NMDA receptors before induction can block LTP49
. It is not clear whether Aβ produces NMDA receptor potentiation50
, either of which could potentially mediate this effect.
In conclusion, we found that overproduction of axonal or dendritic Aβ can lead to a decrease in spine number and plasticity. The effects of Aβ were local and could be modulated by action potentials, nAChR and NMDA receptors. Thus, neurons that overproduce Aβ will control the gain of inputs and outputs to nearby neurons that do not overproduce Aβ. Although this could be a protective physiological mechanism, in excess, it could substantially reduce the function of a circuit.