Alzheimer's disease (AD) is an age-related disorder that threatens to become an epidemic as the world population ages. Neurotoxic oligomers of A␤42 are believed to be the main cause of AD; therefore, disruption of A␤ oligomerization is a promising approach for developing therapeutics for AD. Formation of A␤42 oligomers is mediated by intermolecular interactions in which the C terminus plays a central role. We hypothesized that peptides derived from the C terminus of A␤42 may get incorporated into oligomers of A␤42, disrupt their structure, and thereby inhibit their toxicity. We tested this hypothesis using A␤ fragments with the general formula A␤(x؊42) (x ‫؍‬ 28 -39). A cell viability screen identified A␤(31-42) as the most potent inhibitor. In addition, the shortest peptide, A␤(39 -42), also had high activity. Both A␤(31-42) and A␤(39 -42) inhibited A␤-induced cell death and rescued disruption of synaptic activity by A␤42 oligomers at micromolar concentrations. Biophysical characterization indicated that the action of these peptides likely involved stabilization of A␤42 in nontoxic oligomers. Computer simulations suggested a mechanism by which the fragments coassembled with A␤42 to form heterooligomers. Thus, A␤(31-42) and A␤(39 -42) are leads for obtaining mechanism-based drugs for treatment of AD using a systematic structure-activity approach.Alzheimer's disease ͉ amyloid ␤-protein ͉ inhibitor design A lzheimer's disease (AD) is the predominant cause of dementia and one of the leading causes of death among elderly people. It is estimated that there are currently Ϸ27 million people suffering from AD worldwide (1). Because the world population is aging rapidly, if no cure is found in the near future AD will become an epidemic (2).The amyloid cascade hypothesis proposed that amyloid ␤-protein (A␤) fibrils-an aggregated form of A␤ found in amyloid plaques in the brains of patients with AD-were the neurotoxic agents causing AD (3). However, in recent years, multiple lines of evidence have led to a revision of this view, and today the primary toxins causing AD are believed to be early-forming A␤ oligomers rather than A␤ fibrils (4, 5). This paradigm shift suggests that efforts toward development of therapeutic agents targeting A␤ assembly should be directed at A␤ oligomers rather than fibrils. In particular, genetic, physiologic, and biochemical data indicate that oligomers of the 42-aa form of A␤, A␤42, are most strongly linked to the etiology of AD (6-9) and therefore are a particularly attractive target for inhibitor design.Several groups have reported small-molecule inhibitors of A␤ oligomerization (10-13). The importance of understanding the mechanism of inhibition recently has been highlighted (14) after findings that many small-molecule inhibitors of fibrillogenesis may act nonspecifically, likely making them unsuitable for treating amyloid-related disorders (15). In addition, inhibition of fibril formation may actually lead to stabilization of toxic oligomers (16). Interestingly, when oligomers are stabiliz...

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Although it is generally believed that amyloid beta (Abeta) peptides contribute to the pathogenesis of Alzheimer's disease, the precise role of these peptides in the development of memory loss of Alzheimer's disease, has not been fully understood. The present study examined the effect of several synthetic Abeta peptides on long-term potentiation (LTP), a cellular model of learning and memory, in rat hippocampal slices. Brief perfusion of slices with low concentrations (200 nM or 1 microM) of Abeta(1-42), Abeta(1-40) or their active fragment Abeta(25--35) significantly inhibited LTP induction without affecting the basal synaptic transmission and posttetanic potentiation in the dentate medial perforant path. A similar effect of Abeta(25-35) was also observed in the Schaffer collateral-CA1 pathway. When comparing actions of several Abeta variants derived from Abeta(25-35), the N-terminal sequence of Abeta(25-35) was found necessary for inhibiting LTP. In addition, Abeta variants lacking neurotoxic action and aggregating property were also able to block LTP, suggesting that this effect was neurotoxicity independent. Our findings demonstrated that subneurotoxic concentrations of Abeta peptides could strongly suppress long-term synaptic plasticity in the hippocampus. Such an effect might underlie the memory deficits seen in Alzheimer's disease before neuronal cell loss.

Accumulation of amyloid beta-peptides (Abeta) in the brain has been linked with memory loss in Alzheimer's disease and its animal models. However, the synaptic mechanism by which Abeta causes memory deficits remains unclear. We previously showed that acute application of Abeta inhibited long-term potentiation (LTP) in the hippocampal perforant path via activation of calcineurin, a Ca2+ -dependent protein phosphatase. This study examined whether Abeta could also inhibit Ca2+/calmodulin dependent protein kinase II (CaMKII), further disrupting the dynamic balance between protein kinase and phosphatase during synaptic plasticity. Immunoblot analysis was conducted to measure autophosphorylation of CaMKII at Thr286 and phosphorylation of the GluR1 subunit of AMPA receptors in single rat hippocampal slices. A high-frequency tetanus applied to the perforant path significantly increased CaMKII autophosphorylation and subsequent phosphorylation of GluR1 at Ser831, a CaMKII-dependent site, in the dentate area. Acute application of Abeta1-42 inhibited dentate LTP and associated phosphorylation processes, but was without effect on phosphorylation of GluR1 at Ser845, a protein kinase A-dependent site. These results suggest that activity-dependent CaMKII autophosphorylation and AMPA receptor phosphorylation are essential for dentate LTP. Disruption of such mechanisms could directly contribute to Abeta-induced deficits in hippocampal synaptic plasticity and memory.