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-A beta antibody.
J Clin Invest. 2006 Mar;116(3):825-32.
Please login to recommend the paper.
To make a comment you must login or register.
In short, Bales et al. provide data suggesting that Aβ association with the choline transporter, ChT-1, leads to augmentation of enzyme activity. In the PDAPP mouse hippocampus, this apparently leads to dysregulation of ACh synthesis and release. Treatment of these animals with a monoclonal antibody that selectively interacts with soluble Aβ completely reverses the ACh phenotype. The fact that a conformationally selective antibody, m266, reverses impaired baseline ACh efflux as well as dysregulation of pharmacologically or behaviorally induced ACh efflux suggests that the binding of Aβ to ChT-1 is conformation-dependent. This also indirectly demonstrates that m266 recognizes a toxic form of Aβ in that administration of the antibody, and not other anti-Aβ antibodies, to PDAPP mice selectively reversed the ACh phenotype.
The PDAPP mice have a rather complex phenotype regarding evoked versus baseline ACh efflux. In comparison to wild-type or m266-treated PDAPP, PDAPP hippocampus baseline ACh is reduced, extracellular choline is elevated, behaviorally induced ACh efflux is elevated, and blockade of muscarinic acetylcholine receptors with scopolamine results in reduced ACh release. The authors interpret this as possibly due to enrichment of ChT-1 to a synaptic vesicular pool (thus explaining the enhanced choline transport in synaptosomes) with subsequent inhibition of choline transport or inappropriate distribution of the transporter elsewhere. Impaired ACh biosynthesis, reduced ACh levels overall, lower ACh basal release, excess ACh efflux with behavioral activity, and impaired scopolamine-induced ACh release are attributed to the latter. Further studies should elucidate if ChT-1 distribution is altered under conditions of elevated Aβ.
Based on the work of Cirrito et al., 2005, one might propose an additional mechanism in which synaptic activity stimulates Aβ production, which then interacts with ChT-1 to increase choline uptake and stimulate new ACh synthesis. This, in turn, leads to enhanced ACh release under behaviorally evoked conditions. In vitro experiments similar to the choline uptake studies performed in this work might shed light on the likelihood of this mechanism if ACh levels increase in synaptosomes treated with Aβ1-42.
While it is presumed that the Aβ species used in the choline uptake studies is soluble, it is hoped that future studies will have a more extensive characterization of which conformation(s) bind to the ChT-1 to affect its function and a more direct demonstration that m266 interacts with and neutralizes the same.
If the observations described for PDAPP mice in Bales et al. truly represent AD, it certainly has implications for the timing of AChE treatment. If in early stages of the disease, basal ACh synthesis is impaired and on-demand ACh synthesis is excessive, anti-cholinesterase treatment might not be the most efficacious strategy. It would be interesting to know if cholinesterase therapy in PDAPP mice improves or exacerbates memory performance at young ages.