In many respects, the brain is a black box. The organ where our knowledge is derived is, ironically, also the one where much of the knowledge for its inner workings are lacking. However, researchers have devoted their lives to understanding the enigmatic organ and work tirelessly to prevent diseases that deprive it of its primary functions. For instance, new research from a team of investigators led by scientists at Memorial Sloan Kettering (MSK) has uncovered new findings that show how stress-induced changes in protein connections in the brain contribute to the cognitive decline seen in Alzheimers disease (AD).
Amazingly, the researchers were able to reverse this malfunctioning protein network and its associated cognitive decline in mice, using an experimental drug. Findings from the new studypublished recently in Nature Communications through an article entitled The epichaperome is a mediator of toxic hippocampal stress and leads to protein connectivity-based dysfunctionsuggest a new way to look at how Alzheimers develops in the brain by focusing on protein networks.
The research team used laboratory, mouse, and brain-tissue studies to examine the epichaperomea dysregulated network of proteins that affects how cells communicate and accelerate the course of disease.
To find out why epichaperomes were prevalent in Alzheimers, we used a new omics method, we call chaperomics, that allows us to assess functional outcomes of connectivity changes between normal individuals and those with Alzheimers, explained senior study investigator Gabriela Chiosis, PhD, a professor in the department of molecular pharmacology and chemistryat MSK. This new technology has a profound capacity for high throughput. Although chaperomics generates massive datasets, Chiosis states data analysis is meant to be readily accessible, indicating The bioinformatics platforms are straightforward and easy to comprehend, rather than adding additional complexity to these large protein connectivity-based results.
Various stressorssuch as genetic risk factors, vascular injury, and diabetescan damage brain circuitry in AD. According to this new study, these stressors seem to interact with proteins and contribute to toxic changes that begin in the hippocampus, a brain region involved in learning and memory. The researchers explored how these protein networks stop working properly and can be restored.
We used cellular and animal models as well as human biospecimens to show that AD-related stressors mediate global disturbances in dynamic intra- and inter-neuronal networks through pathologic rewiring of the chaperome system into epichaperomes, the authors wrote. These structures provide the backbone upon which proteome-wide connectivity, and in turn, protein networks become disturbed and ultimately dysfunctional.
Much like faulty wires in a circuit board that lead to network failure, epichaperomes seem to remodel cellular processes that, in turn, rewire protein connections supporting normal brain function. The resulting imbalance in brain circuitrywhich the authors call protein connectivity-based dysfunctionunderlies synaptic failure and other neurodegenerative processes. The researchers studied a cellular model of Alzheimers and a mouse model of the protein tau, as well as human brain tissue, which showed significantly more epichaperomes in individuals who had Alzheimers than in cognitively healthy people.
Based on their discoveries, Chiosis and her colleagues developed a new term to describe this phenomenonprotein connectivitybased dysfunction or PCBD. Many people who study Alzheimers are thinking about circuits in the brain. But theres no clear understanding of how stressors due to aging and the environment change the way proteins interact, noted collaborating scientist and study co-author Stephen Ginsberg, PhD, an associate professor at the Center for Dementia Research at the Nathan Kline Institute and departments of psychiatry, neuroscience & physiology and the NYU neuroscience institute at the NYU School of Medicine. Our research demonstrates that epichaperome formation rewires brain circuitry in Alzheimers by enabling proteins to misconnect, leading to downstream PCBD and cognitive decline.
In the current study, the research team treated young and old mice bred to have Alzheimers with an epichaperome inhibitor they developed, called PU-AD, three times per week for three to four months. The treated mice performed better on memory and learning tests than untreated mice had less tau (a protein seen in AD) and survived longer. Whats more, their brains looked like those of normal mice. PU-AD inhibited the faulty protein networks created by epichaperomes by correcting how the proteins connected and promoting nerve-cell survival.
We show at cellular and target organ levels that network connectivity and functional imbalances revert to normal levels upon epichaperome inhibition, the authors concluded. We provide proof-of-principle to propose AD is a PCBDopathy, a disease of proteome-wide connectivity defects mediated by maladaptive epichaperomes.
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