Paul and colleagues at Eli Lilly and Co., Indianapolis, now report a possible explanation for that surprising result. In a paper published online February 23 in the Journal of Clinical Investigation, the researchers show that the PDAPP mice display an Aβ-dependent decrease in hippocampal acetylcholine (ACh) release, which manifests as a learning deficit. Administration of the m266 anti-Aβ antibody restored cholinergic tone and reversed the learning deficit.

Just as this week’s other news shows that stimulation of the cholinergic system can rein in Aβ production, Paul’s new data suggests that Aβ can be hazardous to ACh levels. The results support the idea that passive immunization of people early in the course of AD might be sufficient to elicit some functional improvement.

To measure cholinergic function in vivo, first author Kelly Bales and colleagues performed in vivo microdialysis measurements of acetylcholine in the hippocampus of free-running PDAPP and control wild-type mice. Under basal conditions, the PDAPP mice showed lower acetylcholine levels than did age-matched controls. When the mice were stimulated, they showed a profound dysregulation in evoked ACh release. Putting the mice into a new cage (environmental stimulation) caused a much higher and prolonged evoked ACh release in the PDAPP mice. In contrast, pharmacological treatment with the muscarinic receptor antagonist scopolamine resulted in much lower ACh release in the transgenic compared to wild-type.

While searching for a reason for the reduction in basal ACh in PDAPP mice, the researchers found an increase in extracellular choline. This led them to examine the effect of Aβ on the choline transporter ChT-1. Coimmunopreciptation experiments indicated that Aβ42 physically associates with ChT-1 in hippocampus. Aβ affected choline transport, but not in the direction expected. In synaptosomes from hippocampus, Aβ treatment caused an increase in choline uptake. The investigators hypothesize that the increase may reflect a compensatory mechanism in response to failed cholinergic signaling.

Whatever the details of the odd brain chemistry of PDAPP mice, all was brought nearly back to normal by administration of the anti-Aβ antibody m266. Whether in microdialysis measures or synaptosome uptake, a shot of m266 antibody was sufficient to restore basal and evoked ACh release, and normalize choline transport.

Normalizing cholinergic signals also affected the mice’s performance in one behavioral test. Mice placed in a new environment run around for a while and eventually settle down, in a process of habituation. Previously, the same workers had shown that PDAPP failed to habituate like wild-type mice, demonstrating a higher locomotor activity throughout the hour-long test (Dodart et al., 1999). Mice treated with the m266 antibody habituated normally, suggesting that returning ACh to normal resulted in restoration of this learning response.

The results uphold the idea that cholinergic defects, thought to underlie memory loss in humans, could result at least in part from a direct “cholinotoxic” effect of Abeta. Previously, Abeta has been shown to bind the alpha7 nicotinic ACh receptor and there have been suggestions that this interaction promotes tau phosphorylation (see ARF related news story). Just how Abeta association with alpha7 or the choline transporter might be linked to the observed ACh dysregulation will be a subject for further study.

The reversal of ACh perturbations by the antibody m266 is promising, but it is important to keep in mind that for all their plaques, these mice do not undergo neurodegeneration, a process that sets in quite early in people with AD. Understanding the limits of reversibility in humans versus mice will be critical to developing anti-Abeta treatments—Pat McCaffrey.

Reference:
Bales KR, Tzavara ET, Wu S, Wade MR, Bymaster FP, Paul SM, Nomikos GG. Cholinergic dysfunction in a mouse model of Alzheimer disease is reversed by an anti-Abeta antibody. J Clin Invest. 2006 Feb 23; [Epub ahead of print] Abstract