Rakez Kayed, PhD, The University of Texas Medical Branch, Galveston, TX, presents his work on tau oligomer-induced high mobility group box 1 (HMGB1) release and its contribution to cellular senescence in tauopathy models, for which he was awarded the Inge Grundke-Iqbal Award For Alzheimer’s Research at AAIC 2022. Previous work has demonstrated tau oligomers to contribute to pathology spreading, neuroinflammation, and cytotoxicity in tauopathies. To further understand the underlying mechanisms of tau oligomer-induced neuroinflammation, the team investigated tau oligomers in astrocytes. Elevated levels of tau oligomers were seen in astrocytes in human Alzheimer’s disease and frontotemporal dementia tissue, as well as htau transgenic mice. It was also noted that the presence of tau oligomers was associated with HMGB1 release, a protein known to be involved in cellular senescence. When cultured astrocytes were exposed to these tau oligomers, they showed HMGB1 release and induction of an inflammatory senescence-associated secretory phenotype (SASP), which mediated paracrine senescence in adjacent cells. Collectively, these findings demonstrate the role of tau oligomers in promoting cellular senescence via HMGB1, which could represent an important pathological mechanism in human tauopathies. This interview took place at the Alzheimer’s Association International Conference (AAIC) 2022 in San Diego, CA.
Transcript (edited for clarity)
Most of the time we focus on neurons and synapses, because the disease mainly affects the memory. But recently a lot of attention, and rightfully so, have been focusing on the immune system. And the astrocyte, the glia, and definitely the neurons are not in a vacuum, they are interacting with these other cell types. So one of my students wanted to look at these tau oligomers in astrocytes. And she did in human tissues, mouse tissues, and she found that they’re there...
Most of the time we focus on neurons and synapses, because the disease mainly affects the memory. But recently a lot of attention, and rightfully so, have been focusing on the immune system. And the astrocyte, the glia, and definitely the neurons are not in a vacuum, they are interacting with these other cell types. So one of my students wanted to look at these tau oligomers in astrocytes. And she did in human tissues, mouse tissues, and she found that they’re there. But the key find, okay, for us, this is descriptive, but still important, maybe it’s like oligomers, they can be transported from neuron to astrocyte, vice versa. So that was the focus. But then the student made an observation that there is association between the presence of these oligomers, and one protein, which is called high mobility group box 1, HMGB1 protein. And we proposed a hypothetical thing, like HMGB1 and oligomers are associated. So this is how it started the whole thing.
And after that, a couple of groups published a lot about astrocyte senescence in tauopathy mouse models. And that was really exciting, but it took us a while to realize that HMGB1 actually is also part of the senescence associated secretory pathway, the SASP. And then it kind of Eureka moment, like oh, maybe this is connected. And this is why we went on our journey to investigate the hypothesis, or at least to test if the oligomers or pathological tau trigger HMGB1 release. HMGB1 is normally in the nucleus. But if it’s released into cytoplasm, then it becomes a bad signal. And this is what we looked at. And we show it in different models in vitro, in vivo.
So basically that was a more mechanistic link between pathological tau and astrocyte senescence. And the problem with senescence is that, once it starts in one cell, they secrete molecules that they spread in the tissue, in the neighborhood. So that was pretty intriguing. And the other thing, which we wanted to focus on, that senescence is also a risk factor in aging. So basically it was clear the more we age the animals, the more senescence we notice for tau transgenic animals.