Controlling the pathological state of dementia: QST finds that autophagy protects neurons in the brain

Group Leader Naruhiko Sahara and researcher Maiko Ono, Department of Functional Brain Imaging, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, and their colleagues have announced, together with Juntendo University and Nagasaki University, that they have clarified that autophagy mediated by the autophagy receptor protein p62 controls the pathological state of dementia by breaking down highly toxic tau oligomers in the tau protein aggregates thought to cause the disease. In a p62-deficient dementia mouse model, the group observed remarkable tau oligomer accumulation in the hippocampus, which is associated with memory, as well as atrophy of the brain and increased inflammation. It is hoped that their results will lead to the development of a treatment method for dementia. These research outcomes were published in the June 5 edition of Aging Cell, an international science journal.

The prevalence of dementia increases as people age, and so this is becoming a social problem in Japan's super-aging society. In dementia, including Alzheimer's disease, abnormal tau protein aggregates build up in neurons and glial cells in the brain. It is thought that neurons are damaged through the aggregation process, which causes cell death.

Normally, the brain's homeostasis is maintained through the two degradation systems of ubiquitin-proteasome and autophagy, which break down unnecessary proteins and their aggregates in cells. In recent years, it has been reported that autophagy is selective and non-selective, and selective autophagy is associated with the breakdown of protein aggregates.

There are multiple types of autophagy receptor proteins, and of these, it has been observed that p62 is also deposited in the characteristic tau lesions of a brain with a neurodegenerative disease. The possibility that this is connected with the degradation of tau lesions (neurofibrillary tangles) has been suggested, but the details were unclear. Neurofibrillary tangles are lesions seen in brain neurons in Alzheimer's disease where abnormally phosphorylated tau protein aggregates undergo fibrosis and are deposited in nerve cytoplasm, and tau proteins are thought to aggregate after undergoing structural change.

From this background the research group created a mouse model for dementia in which abnormal tau proteins build up in the neurons of the brain, removed p62, and investigated the effects of this. The lifespan of a wild mouse is short (around two years), and they do not normally suffer from dementia.

In the dementia mouse model (PS19 mouse), abnormal tau proteins built up in the hippocampus as the mouse aged, the neurons gradually died, and the hippocampus atrophied. In contrast, in the p62-deficient dementia mouse model, the build-up of phosphorylated abnormal tau proteins in the hippocampus increased at a striking rate early on. The researchers learned that atrophy accelerated at a remarkable pace by using MRI to measure the volume of the hippocampus. Moreover, the microglia and astrocytes that govern immunity in the brain were stimulated in the hippocampus, and inflammation increased.

In addition, when the research group carried out a detailed analysis of the types of tau aggregate that were increasingly building up in the hippocampus of the p62-deficient dementia mouse model, they saw that tau aggregates that had undergone high level fibrosis tended to increase. They also learned that the build-up of tau oligomers increased remarkably when compared to the dementia mice. Tau oligomers are polymers in which small numbers of abnormally phosphorylated tau proteins are bonded, and are thought to have an especially high toxicity. In the wild-type mouse, tau oligomer build-up was not observed, even in old age, nor was it seen in a p62-deficient mouse.

Many other autophagy receptor proteins exist, but p62 in particular is highly expressed in the brain, and it is hoped that this could be a target for new drug discovery. In Nagasaki University, which is already involved in the joint research, lecturer Gen Matsumoto has started a screening system for compounds that stimulate p62.

In future, the group expects to verify the effectiveness of the compounds searched for by the screening system. Moreover, they are also simultaneously going ahead with research that will clarify the triggers for the transformation of proteins whose normal functions concern microtubule polymerization and stability into highly toxic tau oligomers.

Journal Information
Publication: Aging Cell
Title: Central role for p62/SQSTM1 in the elimination of toxic tau species in a mouse model of tauopathy
DOI: 10.1111/acel.13615