Abstract
Alzheimer's disease (AD) is characterized by the transition of amyloid-β (Aβ) monomers into toxic oligomers and plaques. Given that Aβ abnormality typically precedes the development of clinical symptoms, an agent capable of disaggregating existing Aβ aggregates may be advantageous. Here we report that a small molecule, 4-(2-hydroxyethyl)-1-piperazinepropanesulphonic acid (EPPS), binds to Aβ aggregates and converts them into monomers. The oral administration of EPPS substantially reduces hippocampus-dependent behavioural deficits, brain Aβ oligomer and plaque deposits, glial γ-aminobutyric acid (GABA) release and brain inflammation in an Aβ-overexpressing, APP/PS1 transgenic mouse model when initiated after the development of severe AD-like phenotypes. The ability of EPPS to rescue Aβ aggregation and behavioural deficits provides strong support for the view that the accumulation of Aβ is an important mechanism underlying AD.
Highlights
Alzheimer’s disease (AD) is characterized by the transition of amyloid-b (Ab) monomers into toxic oligomers and plaques
In addition to the compounds facilitating Ab aggregation, we identified six small molecules that inhibited the formation of Ab oligomers and fibrils[13]
Here we report that (1) a small molecule, EPPS, converts neurotoxic oligomers and plaques into non-toxic monomers by directly binding to Ab aggregates; (2) orally administered EPPS produces a dose-dependent reduction of Ab plaque deposits and behavioural deficits in APP/PS1 TG mice, even when administration was delayed until after the pathology was well established; (3) the beneficial effect of EPPS probably operates through an Ab-related mechanism rather by facilitating cognitive processes; and (4) large doses of EPPS appeared to be well tolerated in initial toxicity studies[6,7,33]
Summary
Alzheimer’s disease (AD) is characterized by the transition of amyloid-b (Ab) monomers into toxic oligomers and plaques. The oral administration of EPPS substantially reduces hippocampus-dependent behavioural deficits, brain Ab oligomer and plaque deposits, glial g-aminobutyric acid (GABA) release and brain inflammation in an Ab-overexpressing, APP/PS1 transgenic mouse model when initiated after the development of severe AD-like phenotypes. Substantial efforts have been devoted to reducing Ab levels, including methods to prevent the production and aggregation of Ab4–7. These approaches effectively prevent the de novo formation of Ab aggregates, existing Ab oligomers and plaques will still remain in the patient’s brain[8,9,10]. As Ab typically begins to aggregate long before the onset of AD symptoms, interventions aimed at disaggregating existing plaques and oligomers may constitute a useful approach to AD treatment, perhaps in parallel with agents aimed at inhibiting aggregate formation[8,9,10,11,12]
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