Amyloid beta dimers/trimers potently induce cofilin-actin rods that are inhibited by maintaining cofilin-phosphorylation.

BACKGROUND: Previously we reported 1 µM synthetic human amyloid beta1-42 oligomers induced cofilin dephosphorylation (activation) and formation of cofilin-actin rods within rat hippocampal neurons primarily localized to the dentate gyrus. RESULTS: Here we demonstrate that a gel filtration fraction of 7PA2 cell-secreted SDS-stable human Aß dimers and trimers (Aßd/t) induces maximal neuronal rod response at ~250 pM. This is 4,000-fold more active than traditionally prepared human Aß oligomers, which contain SDS-stable trimers and tetramers, but are devoid of dimers. When incubated under tyrosine oxidizing conditions, synthetic human but not rodent Aß1-42, the latter lacking tyrosine, acquires a marked increase (620 fold for EC50) in rod-inducing activity. Gel filtration of this preparation yielded two fractions containing SDS-stable dimers, trimers and tetramers. One, eluting at a similar volume to 7PA2 Aßd/t, had maximum activity at ~5 nM, whereas the other, eluting at the void volume (high-n state), lacked rod inducing activity at the same concentration. Fractions from 7PA2 medium containing Aß monomers are not active, suggesting oxidized SDS-stable Aß1-42 dimers in a low-n state are the most active rod-inducing species. Aßd/t-induced rods are predominantly localized to the dentate gyrus and mossy fiber tract, reach significance over controls within 2 h of treatment, and are reversible, disappearing by 24 h after Aßd/t washout. Overexpression of cofilin phosphatases increase rod formation when expressed alone and exacerbate rod formation when coupled with Aßd/t, whereas overexpression of a cofilin kinase inhibits Aßd/t-induced rod formation. CONCLUSIONS: Together these data support a mechanism by which Aßd/t alters the actin cytoskeleton via effects on cofilin in neurons critical to learning and memory.

Certain inhibitors of synthetic amyloid beta-peptide (Abeta) fibrillogenesis block oligomerization of natural Abeta and thereby rescue long-term potentiation.

Recent studies support the hypothesis that soluble oligomers of amyloid beta-peptide (Abeta) rather than mature amyloid fibrils are the earliest effectors of synaptic compromise in Alzheimer's disease. We took advantage of an amyloid precursor protein-overexpressing cell line that secretes SDS-stable Abeta oligomers to search for inhibitors of the pathobiological effects of natural human Abeta oligomers. Here, we identify small molecules that inhibit formation of soluble Abeta oligomers and thus abrogate their block of long-term potentiation (LTP). Furthermore, we show that cell-derived Abeta oligomers can be separated from monomers by size exclusion chromatography under nondenaturing conditions and that the isolated, soluble oligomers, but not monomers, block LTP. The identification of small molecules that inhibit early Abeta oligomer formation and rescue LTP inhibition offers a rational approach for therapeutic intervention in Alzheimer's disease and highlights the utility of our cell-culture paradigm as a useful secondary screen for compounds designed to inhibit early steps in Abeta oligomerization under biologically relevant conditions.

Deciphering the genetic basis of Alzheimer's disease.

A remarkable rise in life expectancy during the past century has made Alzheimer's disease (AD) the most common form of progressive cognitive failure in humans. Compositional analyses of the classical brain lesions, the senile (amyloid) plaques and neurofibrillary tangles, preceded and has guided the search for genetic alterations. Four genes have been unequivocally implicated in inherited forms of AD, and mutations or polymorphisms in these genes cause excessive cerebral accumulation of the amyloid beta-protein and subsequent neuronal and glial pathology in brain regions important for memory and cognition. This understanding of the genotype-to-phenotype conversions of familial AD has led to the development of pharmacological strategies to lower amyloid beta-protein levels as a way of treating or preventing all forms of the disease.