Remembering John Q Trojanowski, in his own words: A life dedicated to discovering building blocks and using them to build bridges of knowledge, collaboration and discovery

Walking through a very crowded field, they decided to take the road less traveled, the “Tau road”, which led them to their first treasure chest and the discovery of Tau as the main component of AD tangles. At that time, the building block of neuritic plaques (amyloid-β) had already been identified by Glenner and Wong, and people’s attention then turned to identifying the building blocks of the second pathological hallmark of AD , neurofibrillary tangles. Although some people suspected Tau as a potential candidate, John and Virginia were eventually the first to succeed in isolating paired helical filaments from tangles and demonstrating that they are composed of the protein Tau.

“I was working on a group of brain proteins that form normal neurofilaments that are very abundant in neurons, and so at that time it was thought that they might be the disease proteins in Alzheimer’s tangles. , but that turned out not to be the case, so, we asked then what forms these tangles? recalls Lee. “We wanted to collaborate and identify the proteins that form the abnormal filaments of the tangles of Alzheimer’s disease , and we decided to go after that – to try and purify the tangles… Using the brains we had collected at our center, we were able to demonstrate that the Alzheimer’s tangles were indeed formed by proteins abnormal tau. “3—Virginia Lee

“Many people had pointed to tau as a candidate, but it was our partnership that led to our success in combining neuropathology with Virginia’s ingenious development of a way to isolate the paired helical filaments that form neurofibrillary tangles, and then to sequence these pathological filaments structures to show that the building blocks of these filaments were tau.3—John Trojanowski

They felt that Tau was neglected and not getting the respect he deserved for no good reason. They became vocal challengers to the amyloid hypothesis, which in its early versions proposed that amyloid formation is the primary event responsible for triggering a cascade of events, including the formation of Tau tangles, which ultimately lead to neurodegeneration and Alzheimer’s disease.

“Tau was quite a controversial discovery, as many researchers at the time believed that the beta-amyloid peptide was the answer to unlocking the secrets of Alzheimer’s disease. The differences between the two schools of thought were likened to a war saint, between the “BAPtists” (those who married the beta-amyloid pprotein theories of Alzheimer’s disease) and the opposing “Tauists”.3—John Trojanowski

They later discovered that Tau pathology is found in many other brain disorders. For them, this was an exciting finding that further supported their hypothesis that Tau was central to NDDs. However, they continued to face skepticism, and the amyloid hypothesis remained the dominant hypothesis and the one that received the most funding.

Tau had a bad reputation for being a spectator and not a real player. It was very difficult to get funding… People were saying if it’s in so many diseases, how can it matter? Maybe it’s just a reaction to damage happening in the brain. He continued: “It was at the very beginning of research on neurodegenerative diseases”5 –John Trojanowski

The discovery of Tau gene mutations in frontotemporal dementia and chromosome 17-linked parkinsonism (FTDP-17) was a game-changer and gave John and Virginia more confidence and tools to defend Tau. But even that was not enough to convince the BAPTists. In 1998, he complained that the neuroscience program at the Neuroscience Society Annual Meeting did not have a session on Tau, but expressed great confidence that this trend was coming to an end and the world would not wouldn’t be able to ignore Tau and other proteins. John was always ahead of the crowd.

“…if you look at the neuroscience program this year, you won’t find any sessions on tau. In the last 5 or 6 years we have fallen into “AD: other” and I think next year you will see in neuroscience a lot of synuclein, a lot of tau and there will be tau session I, II and III ’cause it’s just gotta be a hotbed”1 –John Trojanowski

Their discoveries, perseverance, and the tools they developed have paved the way for future discoveries implicating Tau in the pathology and pathogenesis of several other neurodegenerative diseases. This, combined with the continued failure of amyloid clinical trials and converging evidence pointing to changes in Tau levels and pathology as the best predictors of cognitive decline, has led to Tau transforming from a bystander to a rock star. It took decades, but it was worth it for John and Virginia.

“The religious play on words for these competing hypotheses about what led to brain degeneration in Alzheimer’s disease was a cute thing, but it really borders on the intensity of religious wars – it could get very harsh. But over the years that changed, there were people who said that A-beta explained everything, and then when it didn’t, they said, maybe A-beta is necessary but not sufficient; it’s the trigger… So you have to think of a bullet in a gun you pull the trigger and the bullet goes out but if you try to fix the trigger it won’t change the direction of the shot So if shaking A-beta doesn’t cure the disease, that’s because it may be the trigger and not the bullet that actually kills the neurons in Alzheimer’s.3 –John Trojanowski

Their journey with Tau inspired them to travel to other uncharted territories and discover and make the case for other proteins that later emerged as central players in other neurodegenerative diseases, such as alpha-synuclein in Parkinson’s disease (PD), multiple system atrophy (MSA) and synucleinopathies, and TDP-43 in ALS and MDD proteinopathies.

Among their major scientific achievements are the following.

  • The identification of Tau as the main building block protein of neurofibrillary tangles, one of the two neuropathological hallmarks of Alzheimer’s disease (1991).

  • The co-discovery of alpha-synuclein as a main component of Lewy bodies in PD (in collaboration with Michel Goedert and Maria Grazia Spillantini in 1997) and in glial inclusions in MSA (1998).

  • The identification of TDP-43 as the major building block protein of protein deposits found in the brains of patients with amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) (2006).

  • Develop first-generation models for several neurodegenerative diseases.

  • Developing next-generation models to study the spread of pathology in neurodegenerative diseases by “induce normal proteins to create pathology and spread in the brain”—Virginia Lee.

  • Develop animal models that recapitulate the neuropathological diversity and heterogeneity of neurodegenerative diseases.

  • Advocacy and efforts to increase awareness of NDDs and more funding for research on NDDs and aging.

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