September 30, 2022

New Study Finds That a Certain Protein Helps Protect Against Dementia

New Study Finds That A Certain Protein Helps Protect Against Dementia

Dementia models revealed that the p62 receptor protein can help protect the brain against dementia.

A groundbreaking study reveals the crucial role of the protein p62 in reducing neurodegenerative disorders through selective autophagy.

Cells use selective autophagy or self-degradation of undesired proteins to maintain cellular homeostasis (i.e., a state of balance). This process is controlled by autophagy receptors, which mediate the selection of a target protein that is subsequently “cleared.”

Tau proteins, which play a crucial role in the internal architecture of neurons in the brain, abnormally accumulate within neurons in disorders such as dementia and Alzheimer’s disease. This accumulation of hyperphosphorylated tau proteins (or tau oligomers) in the brains of dementia patients leads to the creation of neurofibrillary tangles (NFTs) and eventually cell death of neurons, leading to the disease’s progressive neurodegenerative symptoms. While tau proteins may be degraded by selective autophagy, the specific mechanism by which this happens is unknown.

However, recent research conducted by experts at Japan’s National Institutes for Quantum Science and Technology demonstrated the crucial role performed by a specific gene—the p62 gene—in the selective autophagy of tau oligomers. The team includes researcher Maiko Ono and group head Naruhiko Sahara from Japan’s National Institutes of Quantum Science and Technology’s Department of Functional Brain Imaging. Their findings were published in the journal Aging Cell.

P62 Protein - New Study Finds That A Certain Protein Helps Protect Against Dementia

Researchers from the National Institutes for Quantum Science and Technology prove that the protein p62 eliminates and prevents the formation of toxic tau protein aggregates and inflammation and degeneration of neurons. Credit: Maiko Ono from National Institutes for Quantum Science and Technology, Japan

Previous studies have reported that the abnormal accumulation of the tau proteins may be selectively suppressed by autophagy pathways, through the p62 receptor protein (which is a selective autophagy receptor protein).

Maiko Ono states, “This protein’s ubiquitin-binding ability helps in the identification of toxic protein aggregates (like tau oligomers), which can then be degraded by cellular processes and organelles.”

This study’s novelty, however, lay in the demonstration of p62’s “neuroprotective” role in a living model, which had never been done before. So, how did the researchers achieve this? They used mouse models of dementia. The p62 gene had been deleted (or knocked out) in one group of these mice, so they did not express p62 receptor proteins.

On studying the brains of these mice using immunostaining and comparative biochemical analyses, an interesting picture was revealed. Neurotoxic tau protein aggregates were found in the hippocampus—the area of the brain associated with memory—and brainstem—the center that coordinates the body’s breathing, heartbeat, blood pressure, and other voluntary processes—of p62 knockout (KO) mice. When we consider this along with the symptoms of dementia, which include memory loss, confusion, and mood changes, these findings make a lot of sense.

MRI scans revealed that the hippocampus of p62 KO mice was degenerated (atrophied) and inflamed. A postmortem assessment of their brains revealed a greater loss of neurons in their hippocampus. Further immunofluorescent studies showed that the abnormal tau species aggregates can cause cytotoxicity leading to inflammation and cell death of neurons in p62 KO mice. Oligomeric tau, specifically, accumulated more in the brains of p62 KO mice.

Overall, the findings of this study prove that by eliminating and, hence, preventing the aggregation of oligomeric tau species in the brain, p62 played a neuroprotective role in models of dementia.

At a time when researchers across the world are trying to develop drugs for dementia and other related neurodegenerative disorders, the findings of this study will be of great importance in providing evidence for the accurate targeting of tau oligomers. The global population of aging humans is increasing each year; hence, the need to develop methods to slow down the onset and progression of various neurodegenerative diseases is also expanding. This study provides a positive step towards addressing that need.

Reference: “Central role for p62/SQSTM1 in the elimination of toxic tau species in a mouse model of tauopathy” by Maiko Ono, Masaaki Komatsu, Bin Ji, Yuhei Takado, Masafumi Shimojo, Takeharu Minamihisamatsu, Eiji Warabi, Toru Yanagawa, Gen Matsumoto, Ichio Aoki, Nicholas M. Kanaan, Tetsuya Suhara, Naruhiko Sahara and Makoto Higuchi, 5 June 2022, Aging Cell.
DOI: 10.1111/acel.13615

The study was funded by the National Institutes of Health, Japan Society for the Promotion of Science, and AMED.