Research on New Protein Inspires Hope for Alzheimer’s Disease

Recent research is illuminating potential treatment strategies to prevent memory loss in patients with Alzheimer’s disease. Scientists at John Hopkins Medical School are investigating Ephexin 5, a protein found in higher concentrations in the brains of individuals with Alzheimer’s disease. Inhibiting this protein in mice appears to prevent the onset of memory loss. Researchers indicate that these findings could eventually facilitate the development of drugs targeting Ephexin 5 to prevent or treat Alzheimer’s symptoms.

A professor in biological chemistry and neuroscience at the medical school published the team’s findings online in the Journal of Clinical Investigation on March 27, 2017. Previous research on Alzheimer’s disease has identified the growth of thick plaques on the brain as a significant indicator of the condition. The novel discovery by the research team is that brain cells overproduce Ephexin 5 in the presence of these plaques. This excessive production limits synaptic connections and contributes to memory loss. The team conducted further studies, revealing that blocking Ephexin 5 in mice, even those with brain plaques, can prevent or halt memory loss. Collectively, the results suggest that both the formation of thick plaques and other factors trigger excessive production of Ephexin 5, which restricts synaptic connections and contributes to the severe memory loss associated with Alzheimer’s.

A drug capable of inhibiting Ephexin 5 production could revolutionize Alzheimer’s treatment.

“Ephexin 5 is an appealing pharmaceutical target because, in otherwise healthy adults, it is scarcely present in the brain,” says a graduate student at the medical school working with the professor. “This implies that inhibiting the protein might result in minimal side effects.”

ADDITIONAL FINDINGS & DISCOVERIES:

Memory issues are not necessarily an inevitable part of aging. Research from Virginia Tech shows that age-related memory loss results from specific molecular changes in the brain, and modifying these processes could restore memory function.

In two studies, Timothy Jarome and his graduate students used gene-editing tools to enhance memory in older rats, which serve as models for studying age-related memory decline. Jarome noted that memory loss affects over a third of individuals over 70 and is linked to Alzheimer's disease. This research reveals that memory decline is associated with specific molecular changes that can be targeted for potential treatments.

Modifying Memory Pathways

The first study, published in Neuroscience, examined K63 polyubiquitination, a process that helps direct protein behavior in brain cells. Aging alters this process in key brain regions: it increases in the hippocampus and decreases in the amygdala. By using CRISPR-dCas13 to adjust these levels, memory improved in older rats.

Reactivating a Dormant Gene

The second study, published in the Brain Research Bulletin, focused on the IGF2 gene, which aids memory formation but diminishes with age. The researchers found that DNA methylation silences IGF2. They used CRISPR-dCas9 to remove these chemical tags, reactivating the gene and significantly improving memory in older rats.

Multiple Molecular Systems

These studies indicate that age-related memory loss arises from multiple molecular changes. Understanding these interconnected systems is essential for addressing memory decline and Alzheimer's disease.

Collaborative Research

Both projects were led by graduate researchers in Jarome's lab and involved collaborations with other universities. Jarome emphasized the importance of graduate-led research in shaping scientific inquiries. The research was funded by the National Institutes of Health and the American Federation for Aging Research.