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Chemical Appears to Restore Memory and Clear Alzheimer’s Protein in Mice

A research team in Korea has tested a chemical in mice genetically altered to develop features of Alzheimer’s, showing it can remove a build-up of protein in the brain associated with the disease as well as rescuing memory and behaviour problems in the animals. The findings are published in the journal Nature Communications on Tuesday 8 December 2015.

Alzheimer’s disease is associated with many abnormal changes in the brain, including the build-up of hallmark proteins amyloid and tau, activation of the immune system and a breakdown in communication between nerve cells. Amyloid is a protein that is normally present in the brain but behaves abnormally in Alzheimer’s, often many years before symptoms show. This abnormal amyloid is sticky and starts to clump together into larger and larger structures – eventually creating large ‘plaques’ that are visible in the brain under a microscope.

Researchers at the Korea Institute of Science and Technology had previously discovered a set of molecules that could either speed up or slow down the formation of amyloid plaques in test tubes in the laboratory. In this study, they explored the effect of one of these compounds – 4-(2-hydroxyethyl)-1-piperazinepropanesulphonic acid (EPPS) – in mice showing features of Alzheimer’s.

Histochemical samples taken from the experiment. The caption best describes the image.

Histochemical analyses of Aβ deposition. Aβs were stained with the 6E10 antibody and ThS. Aβ plaques (first row): green; all Aβs (second row): red; 4,6-diamidino-2-phenylindole (DAPI): blue (as a location indicator). The third and bottom rows show merged images of plaques and Aβs, and plaques and Aβs with DAPI staining. Scale bars, 50 μm. Credit: Kim et al./Nature Communications.

In the first experiment, the team found that administering EPPS to mice in drinking water either before, or at the same time as, the mice were injected with abnormal amyloid protein could rescue problems with memory caused by the protein in the brain. The researchers report that EPPS was not toxic to rodents at the doses used and was able to cross into the brain – a particular challenge when developing new drugs for diseases like Alzheimer’s.

In a second experiment, the researchers gave EPPS to mice genetically engineered to develop a build-up of amyloid in the brain, to model what is seen in human disease. These mice start to develop amyloid plaques in the brain and show problems with memory and behaviour which get progressively worse over time. In contrast to some other studies, which treat animals before the disease has started to take hold, the researchers waited until the mice had developed large amounts of amyloid plaques in the brain and severe memory problems before treating them with EPPS in drinking water for three months.

The results showed that treatment with EPPS improved the performance of the mice in tests of memory and learning compared to untreated animals or healthy mice treated with EPPS. Examination of the brains of the mice showed that EPPS had cleared amyloid plaques from the brain and that this difference was greater in animals that had been treated with higher doses of the chemical. Mice treated with EPPS also showed fewer signs of inflammation in the brain.

When the researchers carried out detailed studies of how EPPS was working in laboratory tests, they found evidence that that the chemical could bind directly to clumps of amyloid, breaking them down even at an early stage when they were first starting to stick together.

Dr Simon Ridley, Director of Research at Alzheimer’s Research UK, said:

“There is currently a strong focus on developing treatments for Alzheimer’s that aim to stop the build-up of the hallmark Alzheimer’s protein, amyloid, in the brain. Although some anti-amyloid drugs are currently in late-stage clinical testing, several trials have also failed and there is much debate as whether this is a suitable approach for a new treatment. Many of the current drugs being explored act to stop the formation of amyloid plaques in the brain which mean they may need to be given early in the disease process.

“This interesting study in mice uses a chemical able to break down Alzheimer’s plaques in the brain after they’ve already formed, potentially presenting a way to circumvent the difficult issue of timing with this treatment approach. While this is an appealing prospect, the research is still at the early stage of being explored in animals. Research in animals is an important step in developing any new treatment, but we’ll need to see the findings translated into clinical studies in people before we could know the potential of EPPS to treat Alzheimer’s in humans.

“With no new treatments for Alzheimer’s licensed since 2002, we urgently need to capitalise on promising early science to make sure it’s progressed as quickly as possible towards clinical testing. Alzheimer’s Research UK has launched several large initiatives, including our Drug Discovery Alliance, to ensure that positive early findings can be moved towards new treatments for diseases like Alzheimer’s more quickly.”

About this Alzheimer’s disease research

Source: Alzheimer’s Research UK
Image Credit: The image is credited to Kim et al./Nature Communications
Original Research: Full open access research for “EPPS rescues hippocampus-dependent cognitive deficits in APP/PS1 mice by disaggregation of amyloid-β oligomers and plaques” by Hye Yun Kim, Hyunjin Vincent Kim, Seonmi Jo, C. Justin Lee, Seon Young Choi, Dong Jin Kim & YoungSoo Kim in Archives of Clinical Neuropsychology. Published online December 8 2015 doi:10.1038/ncomms9997


Abstract

EPPS rescues hippocampus-dependent cognitive deficits in APP/PS1 mice by disaggregation of amyloid-β oligomers and plaques

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.

“EPPS rescues hippocampus-dependent cognitive deficits in APP/PS1 mice by disaggregation of amyloid-β oligomers and plaques” by Hye Yun Kim, Hyunjin Vincent Kim, Seonmi Jo, C. Justin Lee, Seon Young Choi, Dong Jin Kim & YoungSoo Kim in Archives of Clinical Neuropsychology. Published online December 8 2015 doi:10.1038/ncomms9997

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