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 Aβ dimers and trimers (Aβd/t) induces maximal neuronal rod response at ~250 pM. This is 4,000-fold more active than traditionally prepared human Aβ oligomers, which contain SDS-stable trimers and tetramers, but are devoid of dimers.

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).

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.