11 July 2009. The α7 nicotinic acetylcholine receptor (α7nAChR) binds the amyloid-β peptide (Aβ) with high affinity (Wang et al., 2000), and has been implicated in Aβ internalization, stimulation of tau phosphorylation (see ARF related news story on Wang et al., 2003), and downregulation of synaptic glutamate receptors in response to Aβ (see ARF related news story on Snyder et al., 2005). Adding to these in vitro studies, new in vivo data from Steve Heinemann’s lab at the Salk Institute in La Jolla, California, published in the July 8 issue of the Journal of Neuroscience, puts the α7 receptor on the pathway to neuronal dysfunction and memory problems in response to Aβ in a mouse model of AD. By crossing α7nAChR knockout mice with animals expressing mutated human amyloid precursor protein (APP), the researchers found that lack of α7 protects the mice from synaptic loss, restores normal long-term potentiation, and improves their performance in the Morris water maze, all without affecting Aβ levels.
The results support the idea that α7nAChR (α7) is a key mediator of Aβ action, and suggest that receptor could be a good drug target. Many pharma companies are working on α7 agonists that would act as cognitive enhancers by augmenting acetylcholine signaling, but the current study offers an alternative therapeutic path that would involve interrupting α7 signaling, or at least blocking access of the receptors to Aβ.
In the study, first author Gustavo Dziewczapolski found that deletion of the α7 gene in the background of APP overexpression (the PDAPP J9 mouse) improved the performance of adult animals in the Morris water maze. While 13- to 16-month-old APP mice did poorly in the memory test, age-matched APP/ α7 KO mice performed more like normal animals. When Dziewczapolski looked at brain tissue, he found that older PDAPP mice showed approximately a 20 percent reduction in the synaptic marker synaptophysin or the dendritic marker MAP2 in frontal cortex and hippocampus, but both markers were preserved in the α7 KO/APP mice. An increase in glial fibrillary acidic protein, a marker of inflammation, in the cortex of APP mice was also reduced in the α7 knockout mice. The effects carried over to neuron function as well. Defects in long-term potentiation measured in hippocampal slices from the APP mice were gone in the APP/α7 knockouts.
The effects were not due to changes in Aβ or plaque load: Expression of amyloid precursor protein and Aβ peptide levels were no different between the strains. The results indicate that without α7, the mice are resistant to Aβ-induced synaptic loss and behavioral changes.
How might this happen? The paper does not settle the question of mechanism, but one possibility is decreased internalization of Aβ (Nagele et al., 2002), which could prevent any toxic actions of intracellular Aβ. “We all think of extracellular Aβ, but intracellular Aβ could be important too,” Dziewczapolski told ARF. “Measuring intracellular Aβ is technically difficult, but we are trying to develop a way to do this. Our next step is to see if we have less intracellular Aβ.”
Alternatively, the α7 receptor has been shown to play a role in the downregulation of NMDA receptors at synapses in response to Aβ. The investigators did measure overall levels of NMDA receptor in brain tissue, and saw no change. That does not rule out changes in cell surface receptor levels, another parameter the researchers are planning to look at.
The idea of using an α7 antagonist in AD seems to run counter to the current interest in α7 agonists for neuroprotection and cognitive enhancement in AD and other diseases. In addition, recent findings showed that low concentrations of Aβ enhance LTP via the α7 receptor (see ARF related news story on Puzzo et al., 2008). However, the authors suggest that positive interactions under normal conditions may turn to pathological effects under conditions where Aβ is elevated. “This is probably the most controversial part of the paper,” Dziewczapolski said, “But we think that in cases where Aβ42 is high, it will be important to block the α7 receptor with an antagonist.” In addition, it is possible that even an agonist could act to antagonize the effects of Aβ, Dziewczapolski explained, if the compound blocks Aβ binding or stimulates receptor internalization.
In favor of the α7 receptor as a target, recent work identified a novel α7β2 nACh receptor dimer that was especially sensitive to Aβ (see ARF related news story). Another recent report provided evidence that receptor levels hold steady in the course of AD (see ARF related news story on Ikonomovic et al., 2009), in contrast to previous reports that α7 receptors were lost.
The caveat to the study, Dziewczapolski cautions, is that the α7/APP animals lack the α7 receptor from birth, so the researchers cannot rule out developmental effects. The more definitive experiment will be to do conditional knockouts, and to assess the results of silencing the receptor after AD pathology has commenced.—Pat McCaffrey.
Dziewczapolski G, Glogowski CM, Masliah E, Heinemann SF. Deletion of the alpha7 nicotinic acetylcholine receptor gene improves cognitive deficits and synaptic pathology in a mouse model of Alzheimer's disease. J Neurosci. 2009 Jul 8;29(27):8805-1. Abstract