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Mouse Model Confirms Importance of Amyloid β Peptide in AD Research

The amyloid precursor protein (APP) being cleaved by gamma and beta secretase and setting the beta amyloid peptide free

The number of Americans living with Alzheimer’s disease is expected to nearly triple by 2060. This statistic is alarming, but researchers are constantly working to slow the disease’s progression and improve symptoms in Alzheimer’s patients. Now, Science Daily reports that experts found that blocking a specific protein could improve Alzheimer’s symptoms. The researchers used the contextual fear conditioning test to validate the importance of the amyloid β peptide (Aβ) for the development of cognitive deficits.

The amyloid precursor protein (APP) being cleaved by gamma and beta secretase and setting the beta amyloid peptide free

The Amyloid β Peptide: A Key Mystery in Alzheimer’s Research

Science Daily reports on the research, which was conducted at Japan’s RIKEN Center for Brain Science (CBS) and published in Molecular Psychiatry. The team’s goal was to assess how or why the Aβ peptide accumulates in the brain of Alzheimer’s patients. To accomplish this, they developed a mouse model of the disease, breeding mice with Aβ accumulation and memory deficits similar to those seen in humans with Alzheimer’s disease. Studying the mouse model, the RIKEN team discovered several key events that led to the formation of Aβ plaques.

Why Are Aβ Plaques Formed?

The research team discovered that the mouse model showed reduced levels of the enzyme neprilysin, which is actually caused by reduced levels of somatostatin, a hormone. In a startling discovery, the RIKEN team identified the connection between the two: the protein α-endosulfine, or ENSA. The team found that ENSA reduced neprilysin activity; thus, mice with low somatostatin levels showed abnormally high levels of ENSA. In other words, somatostatin helps keep ENSA in check, which keeps neprilysin levels high. Those high neprilysin levels destroy Aβ before it can accumulate and create plaques. With this in mind, the team hypothesized that inhibiting ENSA could benefit Alzheimer’s patients.

Exploring ENSA in Mouse Models

To test the effect of ENSA inhibition, the team created ENSA knockout mice and then bred them with the original Alzheimer’s mouse model. As expected, the new mice showed much lower Aβ accumulation than the original mouse model. Still, the scientists weren’t sure exactly why. Science Daily writes that early tests showed that “ENSA blocks a potassium channel in the hippocampus, a part of the brain needed for making and recalling memories.” To test this, the researchers would have to figure out how to help that channel stay open, potentially combatting the presence of excess ENSA. The team decided to feed the mice diazoxide, a drug that activates that channel. The team then needed to complete one final, crucial step: testing the mice’s memories via a contextual fear conditioning test.

Using a Contextual Fear Conditioning Test

A contextual fear conditioning test is a common research method that assesses how mice learn and remember an association – specifically, an association between environmental cues and aversive experiences, like an electric stimulus. This particular test is outlined in the original research published in Molecular Psychiatry. Before the start of the test, the mice were put in a white noise box. The mice were then placed in a sound-attenuating chamber and allowed to explore. While in the chamber, the mice received an electric stimulus and were conditioned with the same treatment daily for four days. The goal: to test whether the mice anticipated the stimulus, thus assessing the role of ENSA in their memory function.

Contextual Fear Conditioning Test Results

The research team found that, while the untreated Alzheimer’s disease mouse models – the mice without ENSA inhibition – continued to show signs of poor memory, the treated mice performed as well as healthy mice without Alzheimer’s markers. In other words, eliminating or blocking the ENSA protein reduced symptoms associated with Alzheimer’s. That has major implications for Alzheimer’s treatment. “Our findings point directly to a potential way of preventing and treating Alzheimer’s disease,” says study first author Naoto Watamura, explaining that drug therapy that aims to block ENSA activity could be a more effective and cheaper treatment than current Alzheimer’s treatments.


The contextual fear conditioning test used in this study is a powerful tool when exploring memory. This is particularly true as researchers race to improve treatments for conditions like Alzheimer’s disease.

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