Study preserves memory in mice, offering promising new basis for active immunization against Alzheimer’s disease

Summary: The corn-derived MetO-rich protein, when injected, induces the immune system to produce antibodies against the MetO component of beta-amyloid. Older mice injected with the MetO-rich protein showed a 50% improvement in memory compared to control animals. The findings could be key to the development of a potential vaccine against Alzheimer’s disease.

Source: University of Kansas

During experiments in animal models, researchers at the University of Kansas have discovered a possible new approach to immunization against Alzheimer’s disease (AD).

Their method uses a recombinant methionine-rich (Met) protein derived from corn that was then oxidized in vitro to produce the antigen: methionine sulfoxide-rich protein (MetO). This antigen, when injected into the body, induces the immune system to produce antibodies against the MetO component of beta-amyloid, a protein toxic to brain cells and thought to be a hallmark of Alzheimer’s disease.

The results have just been published in the peer-reviewed open-access journal Antioxidants.

“As we age, we have more oxidative stress, and then beta-amyloid and other proteins accumulate and oxidize and clump together – these proteins resist being broken down or eliminated,” the researcher said. principal Jackob Moskovitz, associate professor of pharmacology and toxicology at the KU School of Pharmacy.

“In a previous study published in 2011, I injected mouse models of Alzheimer’s disease with a similar protein rich in methionine sulfoxide and showed about a 30% reduction in amyloid plaque load. in the hippocampus, the main region where damage in Alzheimer’s disease occurs.”

The MetO-rich protein used by Moskovitz for vaccination of AD model mice is able to induce the immune system to produce antibodies against proteins containing MetO, including beta-amyloid harboring MetO.

The introduction of corn-based MetO-rich protein (antigen) encourages the body’s immune system to produce and deploy the antibodies against MetO to previously tolerated MetO-containing proteins (including MetO-beta-amyloid), and ultimately reduce levels of toxic substances. forms of beta-amyloid and other possible proteins in the brain.

In the new follow-up study, Moskovitz and his co-authors injected the MetO-rich protein into 4-month-old AD model mice that were genetically engineered to develop the familial form of Alzheimer’s disease. Subsequent tests showed that this approach stimulated the immune system of mice to produce antibodies that could attenuate the presence of AD phenotypes at older ages (10-month-old mice).

“This treatment induced the production of anti-MetO antibodies in the blood plasma which shows a significant titer until at least 10 months of age”, according to the authors.

Moskovitz’s KU co-authors on the antioxidant study are Adam Smith, assistant professor of pharmacology and toxicology; Kyle Gossman and Benjamin Dykstra, graduate students in Smith’s lab; and Philip Gao, director of the protein production group at the Del Shankel Structural Biology Center.

In a series of tests, the KU researchers assessed the memory of injected mice compared to similar mice that did not receive the corn-based methionine sulfoxide.

“We measured short-term memory capacity through a ‘Y’ maze, and that’s very important in Alzheimer’s disease – because when people get Alzheimer’s disease, their short-term memory goes away, while the old memories are still there,” Moskovitz said.

“You put a mouse in a ‘Y’ shaped maze so it can go either the left arm or the right arm. But then you introduce a third arm in the middle, and if they recognize the third arm as new, they’ll spend more time exploring that new arm because they’re curious. If they don’t even notice there’s a third arm – because they forget about it the minute after seeing it – they’ll spend more time right or left.

According to Moskovitz, there was about a 50% improvement in the memory of mice injected with the protein rich in methionine sulfoxide (MetO) compared to the control.

In another experiment, mice were tasked with locating a platform in a water maze.

“We gave them six days to learn, and even those with Alzheimer’s eventually learned the location of the platform – but we found that after the second day there was a big difference, antigen-injected mice learn much faster than unimmunized mice,” Moskovitz said.

“Then we take the platform out to see if they remember where the platform was just from memory, not by looking. And again, we saw a big difference. Mice immunized against the antigen remember and spend more time near the platform on which they were trained compared to unimmunized control mice.

In addition to improved short-term memory, the study showed that mice injected with antigen had better long-term memory abilities, reduced levels of beta-amyloid in blood plasma and brain , as well as “reduced beta-amyloid load and MetO accumulations in astrocytes in the hippocampal and cortical regions; reduced levels of activated microglia; and elevated antioxidant capacities (due to better nuclear localization of the transcription factor Nrf2) in the same regions of the brain.

It shows a brain
In the new follow-up study, Moskovitz and his co-authors injected the MetO-rich protein into 4-month-old AD model mice that were genetically engineered to develop the familial form of Alzheimer’s disease. Image is in public domain

The researchers found that the data collected in the study is likely translational, suggesting that active immunization “may provide the ability to delay or prevent the onset of Alzheimer’s disease.”

Moskovitz said such immunization could be given to people because the risk of Alzheimer’s disease increases later in life, “around when people are told to go for a colonoscopy for the first time in 50s or 60s,” he said. “Further booster shots could keep vaccination going, a process people are so familiar with from COVID vaccines.”

Active immunization would represent an improvement over current passive immunization regimens because the methionine sulfoxide antigen stimulates the immune system to produce its own antibodies. In passive immunization, antibodies are injected directly into the body but can have severe toxic side effects (such as cerebral encephalitis) and be subject to rejection by the immune system as non-self antibodies over time. weather.

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Moskovitz said the next steps in this line of research would be to conduct preclinical and clinical trials in humans in conjunction with sponsorship from interested pharmaceutical companies.

About this Alzheimer’s Disease and Pharmacology Research News

Author: Brendan Lynch
Source: University of Kansas
Contact: Brendan Lynch – University of Kansas
Picture: Image is in public domain

Original research: Free access.
Protective effects against the development of Alzheimer’s disease in an animal model by active immunization with a protein antigen rich in methionine sulfoxideby Jackob Moskovitz et al. Antioxidants


Abstract

Protective effects against the development of Alzheimer’s disease in an animal model by active immunization with a protein antigen rich in methionine sulfoxide

The brain in Alzheimer’s disease (AD) is subjected to severe oxidative attack by reactive oxygen species which can lead to the oxidation of methionine. Oxidation of only methionine (Met35) of beta-amyloid (Aβ), and possibly methionine residues from other extracellular proteins, may be one of the first events contributing to the toxicity of Aβ and other proteins in vivo.

In the present study, we immunized AD (APP/PS1) transgenic mice at 4 months of age with a recombinant protein rich in methionine sulfoxide (MetO) from Zea mays (antigen).

This treatment induces the production of anti-MetO antibodies in the blood plasma which shows a significant titer until at least 10 months of age.

Compared to control mice, mice injected with antigen exhibited the following significant phenotypes at 10 months of age: better short and long memory abilities; Reducedβ blood plasma and brain levels; Reducedβ load and accumulations of MetO in astrocytes of the hippocampal and cortical regions; reduced levels of activated microglia; and high antioxidant capacities (thanks to a better nuclear localization of the Nrf2 transcription factor) in the same regions of the brain.

These data collected in a preclinical model of AD are probably translational, showing that active immunization could provide the possibility of delaying or preventing the onset of AD.

This study represents a first step towards the complex way of starting clinical trials in humans and making the additional confirmations necessary to move in this direction.

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