This paper is interesting not only conceptually but also technically, i.e., the protocol employed for detecting Abeta dodecamers will be universally useful for a number of AD researchers.

View all comments by Takaomi Saido

An interesting study that suggests a link between Abeta oligomers, GSK-3beta and tau hyperphosphorylation.

View all comments by Dominic Walsh

Aβ oligomers have been around for as long as Aβ (Masters et al., 1985). Their significance and their relationship with fibrils has been a longstanding question that is only now becoming clearer as techniques improve. The first conformation-dependent antibodies that we made (Yang, 1995) recognized soluble oligomeric species but not monomer or APP, and these antibodies stain plaques intensely, suggesting that they are conformationally related to fibrils. Our later antibody, A11, showed that there are also oligomers that have a conformation that is distinct from fibrils. On our poster, 422.20, we compared the fibril-specific and oligomer-specific antibodies and showed that they recognize separate and distinct species, and yet on Western blots these soluble oligomers run at the same size (~50 K–200 K). This indicates that there are two distinct types of soluble oligomers and that size is a poor indicator of whether something is fibrillar or prefibrillar.

Recent research is beginning to...  Read more

Aβ oligomers have been around for as long as Aβ (Masters et al., 1985). Their significance and their relationship with fibrils has been a longstanding question that is only now becoming clearer as techniques improve. The first conformation-dependent antibodies that we made (Yang, 1995) recognized soluble oligomeric species but not monomer or APP, and these antibodies stain plaques intensely, suggesting that they are conformationally related to fibrils. Our later antibody, A11, showed that there are also oligomers that have a conformation that is distinct from fibrils. On our poster, 422.20, we compared the fibril-specific and oligomer-specific antibodies and showed that they recognize separate and distinct species, and yet on Western blots these soluble oligomers run at the same size (~50 K–200 K). This indicates that there are two distinct types of soluble oligomers and that size is a poor indicator of whether something is fibrillar or prefibrillar.

Recent research is beginning to show that some of the species different investigators study are more similar than previously appreciated. For example, by their original definition as stable, low MW oligomers (dimer to tetramer), ADDLs appeared to be different from the oligomers other investigators had reported, including our lab (we called them “micelles” in 1994; see Soreghan et al.), Peter Lansbury’s (who called them “protofibrils” in 1997; see Harper et al.), and David Teplow (who also called them protofibrils in 1997; see Walsh et al.). Additional work since then has shown that ADDLs are similar to these oligomers.

Making all relevant antibodies widely available for research purposes, as A11 is, would further accelerate efforts at comparison and independent confirmation.

References:
Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A. 1985 Jun;82(12):4245-9. Abstract

Yang AJ, Knauer M, Burdick DA, Glabe C. Intracellular A beta 1-42 aggregates stimulate the accumulation of stable, insoluble amyloidogenic fragments of the amyloid precursor protein in transfected cells. J Biol Chem. 1995 Jun 16;270(24):14786-92. Abstract

Soreghan B, Kosmoski J, Glabe C. Surfactant properties of Alzheimer's A beta peptides and the mechanism of amyloid aggregation. J Biol Chem. 1994 Nov 18;269(46):28551-4. Abstract

Harper JD, Wong SS, Lieber CM, Lansbury PT. Observation of metastable Abeta amyloid protofibrils by atomic force microscopy. Chem Biol. 1997 Feb;4(2):119-25. Abstract

Walsh DM, Lomakin A, Benedek GB, Condron MM, Teplow DB. Amyloid beta-protein fibrillogenesis. Detection of a protofibrillar intermediate. J Biol Chem. 1997 Aug 29;272(35):22364-72. Abstract

View all comments by Charles Glabe

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...  Read more

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.

References:
Cirrito JR, Yamada KA, Finn MB, Sloviter RS, Bales KR, May PC, Schoepp DD, Paul SM, Mennerick S, Holtzman DM. 2005. Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron. 48(6):913-22. Abstract

View all comments by Kelly Dineley