As the amyloid pathology is shifting away from blaming predominantly amyloid plaques to now pointing a second accusing finger to smaller, non-deposited aggregates of the Aβ peptide, several labs are racing to show exactly what these small suspects might be doing, especially around synapses, and just how they might be toxic. For example, Bill Klein of Northwestern University in Chicago has a series of presentations here in Orlando on his lab’s attempt to take the existing data into the context of neurons and in vivo.
His group is extending their 1998 findings that small Aβ42 oligomers, which they call Aβ-derived diffusible ligands, or ADDLs, (see Lambert et al.) are neurotoxic. On Sunday here at the Neuroscience Conference, Kirsten Viola presented a poster suggesting that, on cultured rat embryonic neurons and human neural precursor cells, ADDLs bind specifically and form distinct little clusters. The authors call these dots "puncta," as clusters of synaptic proteins are frequently referred to. (The ADDL puncta did not colocalize with classic synaptic markers such as synaptophysin or the NGF receptor, however.)
At about a quarter of a micron in size, these dots are near the resolution limit of the light microscope, making further structural analysis in that way difficult. However, the clustering seems to fit with findings from Hilal Lashuel and Peter Lansbury that annealed, higher-order structures of Aβ oligomers can form ring-like structures in the electron microscope and their hypothesis that these might insert into neuronal membranes and form pathologic pores (see Lansbury interview).
Viola et al. saw the puncta on all cell surfaces but they appeared particularly dense along the neuron’s processes, including the neurite tips and growth cones. Further, immunocytochemistry, western blots, and immunoblots of membrane preparation from the cultured cells found that the ADDL puncta colocalized with phosphorylated FAK-YP, a protein previously linked to LTP and Aβ toxicity. The presence of ADDLs appeared to increase the number of FAK-YP puncta by about 100 sites per neurons. Finally, the poster reported that ADDLs appear to bind a novel toxin receptor, which remains unidentified.
Klein’s group will present three more posters on ADDLs on Wednesday, so watch this space for continued coverage by our guest writer, Brenda Patoine.
On the question of how ADDLs might pass their neurotoxic signal on inside the neuron, Lennart Mucke’s group also presented a poster yesterday that implicated more deeply the tyrosine kinase Fyn and its downstream pathways. The link had been made in brain slice experiments previously. Crossing human mutant APP-transgenic mice with Fyn knockout mice decreased the synaptic pathology that the scientists see in those Aβ-overproducing mice when Fyn is present.—Gabrielle Strobel
- Scheinfeld MH, Roncarati R, Vito P, Lopez PA, Abdallah M, D'Adamio L. Jun NH2-terminal kinase (JNK) interacting protein 1 (JIP1) binds the cytoplasmic domain of the Alzheimer's beta-amyloid precursor protein (APP). J Biol Chem. 2002 Feb 1;277(5):3767-75. PubMed.