Modified protein can prevent Alzheimer’s disease in mice

Summary: Researchers injected a modified segment of the amyloid precursor protein into mouse models of Alzheimer’s disease. The treatment appeared to reverse a number of the cognitive and memory problems associated with the neurodegenerative disease.

Source: University of Chicago

The amyloid precursor protein has always been villainized as a major cause of Alzheimer’s disease. One of its fragments, the amyloid-beta peptide, can break off and accumulate in the brain, giving rise to the puffy white globs known as senile plaques that are a hallmark of the disease.

In a study published recently in the journal Cell Reports, however, researchers at the University of Chicago have redeemed APP as an unlikely hero, uncovering its extended role in brain signaling that can prevent the development of Alzheimer’s disease in mice.

So, when does APP take on the mantle of hero versus swooping in as the villain in the tragic tale of Alzheimer’s disease?

A long-neglected segment

For years, researchers have mainly paid attention to APP for the Aβ segment encoded in the amino acid sequence, like a dormant monster waiting to be unleashed. In the new research, however, Angèle Parent, associate professor of neurobiology, and her team demonstrated that the other sections of a chopped-up APP strand matter too. One section plays a crucial role in consolidating spatiotemporal learning and memory in the brain, to the extent that it can prevent the onset of Alzheimer’s disease under the right circumstances.

This long-neglected segment, when tethered to the cell membrane, can participate in a signaling mechanism that triggers the formation of new memories. To promote this tethering, Parent and team fashioned a sticky lipid anchor protein from natural APP. This modified APP segment, called the mAICD, is simple in structure but has enormous functional consequences. Six months after newborn mice were injected with a virus that encouraged a high expression of mAICD in the brain, the results were surprising.

These mice were genetically engineered to be afflicted with aggressive Alzheimer’s disease at a young age. Normally, they would have suffered from the advanced symptoms of the disease as young as six months old (equivalent to a young adult in humans), if not for the extra mAICD supplied by the researchers.

This shows neurons

Neurons in the brain of a mouse with Alzheimer’s disease. New research from UChicago shows how a modified piece of one protein can prevent the disease in mice. The image is credited to NIH, Lennart Mucke, University of California, San Francisco.

After the injection, Parent and her team tested the mice’s ability to form spatiotemporal memories. Mice are curious but fickle creatures: familiarity is usually met with indifference. Equipped with a generous helping of mAICD, these mice successfully recalled—or ignored—objects and places previously explored. On the other hand, the control mice with Alzheimer’s who expressed a less interactive version of mAICD, did not recognize supposedly familiar objects and locations at all. They were already gripped by the jaws of the disease.

“When we looked at the mice with the mAICD, they became almost normal,” Parent said. It was as if these mice had never showed signs of Alzheimer’s.

The dark horse jack-of-all-trades

This humble lipid anchor protein was able to keep Alzheimer’s disease at bay in these mice, as long as its expression starts during the brain development stage. The researchers are currently investigating the effects of the same mAICD intervention in the brains of adult mice already afflicted with Alzheimer’s.

“If you’re are born with the Alzheimer’s disease genes, you don’t necessarily have memory problems when you’re young. All that happens much later,” Parent said. “By then, when you already have problems with your memory, will an mAICD boost be able to help you?”

Indeed, the diversity of APP’s functions has exceeded the expectations of earlier researchers. By participating in complex nerve machinery, APP can stimulate the growth of new neurons and strengthen synaptic activity by triggering a series of events associated with memory consolidation. At the same time, APP may also produce Aβ to diminish these memories.

With its numerous and occasionally contradictory functions, this “all-purpose protein,” as Parent fondly calls it, plays many roles: the villain, the redeemed hero, the dark horse, or a jack-of-all-trades. Nevertheless, Parent expects it to star as a coveted memory molecule for its power to form and erase memories in this Cinderella Story.

About this neuroscience research article

Source:
University of Chicago
Media Contacts:
Shi En Kim – University of Chicago
Image Source:
The image is credited to NIH, Lennart Mucke, University of California, San Francisco.

Original Research: Open access
“APP-Mediated Signaling Prevents Memory Decline in Alzheimer’s Disease Mouse Model”. Angèle Parent et al.
Cell Reports. doi:10.1016/j.celrep.2019.03.087

Abstract

APP-Mediated Signaling Prevents Memory Decline in Alzheimer’s Disease Mouse Model

Highlights
• Membrane retention of APP C-tail preserves spatial memory in Alzheimer’s disease model
• APP interaction with GαS attenuates amyloidogenic APP processing
• A self-regulatory component of APP promotes APP processing at the cell surface
• Sustained APP signaling modifies the course of Alzheimer pathology

Summary
Amyloid precursor protein (APP) and its metabolites play key roles in Alzheimer’s disease (AD) pathophysiology. Whereas short amyloid-β (Aβ) peptides derived from APP are pathogenic, the APP holoprotein serves multiple purposes in the nervous system through its cell adhesion and receptor-like properties. Our studies focused on the signaling mediated by the APP cytoplasmic tail. We investigated whether sustained APP signaling during brain development might favor neuronal plasticity and memory process through a direct interaction with the heterotrimeric G-protein subunit GαS (stimulatory G-protein alpha subunit). Our results reveal that APP possesses autonomous regulatory capacity within its intracellular domain that promotes APP cell surface residence, precludes Aβ production, facilitates axodendritic development, and preserves cellular substrates of memory. Altogether, these events contribute to strengthening cognitive functions and are sufficient to modify the course of AD pathology.

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