Götz discoveries
At the beginning of his career, Professor Jürgen Götz contributed mainly to developmental biology, moving his focus to neurodegenerative research in the early 1990s. Götz has been working in the therapeutic ultrasound space since 2014, with several major contributions to the field. In both the dementia and ultrasound space, Professor Götz is recognised as a key opinion leader reflected by several reviews in the Nature Reviews series.
Proving the amyloid cascade hypothesis in Alzheimer's disease (Science 2001)
In 2001, we experimentally provided proof for the central hypothesis of how the disease process is initiated in Alzheimer’s disease, a concept known as the 'amyloid cascade hypothesis'. This study is highly cited and has been listed as a landmark discovery on the Alzforum website.
Knowing what causes and drives Alzheimer’s disease provides a handle to ultimately combat a disease for which there is no cure.
A century earlier, Alois Alzheimer, in his landmark discovery, described amyloid plaques and tau tangles as the hallmark lesions of a disease that would eventually be named after him. However, how Aβ and tau interact has only gradually been revealed, and the amyloid cascade hypothesis was developed in the 1990s, placing Aβ upstream of tau in a pathocascade. In a breakthrough research achievement, Professor Götz showed that Aβ is indeed upstream of tau, causing the latter to aggregate into insoluble filaments. This major advance was made possible by using, for the first time, a combined transgenic and transplantation approach.
This advance was made possible by novel transgenic mouse models of Alzheimer’s disease, a research field Götz pioneered. He was the first to establish a tau transgenic mouse model to achieve a pre-tangle pathology. From here, Professor Götz established models with a more advanced pathology, which showed that tau aggregation can cause degeneration as evidenced, for example, by Wallerian degeneration. The identification of pathogenic mutations in the gene encoding tau in frontotemporal dementia then opened the field to the development of more robust tangle-forming experimental animal models. This work also resulted in two patented protocols of amyloid-β-mediated tau filament formation.
For amyloid to be toxic in Alzheimer’s brains it requires the protein Tau (Cell 2010)
The above work placed tau downstream of amyloid-β in the ‘amyloid cascade hypothesis’, but it was later revealed that the protein tau is by no means an innocent bystander. In a major development, Professor Götz and his team demonstrated that tau is, in fact, required for amyloid-β to exert its toxic effects on neurons. They were able to link the two key players via an enzyme called fyn and a receptor called NMDAR (which incidentally is antagonised by the Alzheimer’s drug Memantine).
The interactions which were revealed between NMDAR, tau and fyn offer avenues for therapeutic intervention. The team’s findings caused a major paradigm shift in the field and resulted in tau gaining attraction as a therapeutic target and the development of two patents.
Amyloid activates the production of tau protein, whereas Tau blocks the machinery which makes proteins (EMBO J 2017 & 2019)
Professor Götz and his team have a major interest in understanding what drives the accumulation of proteins in an aggregated form as this is the unifying feature of neurodegenerative disorders. They also have an interest in understanding where exactly in the cell these processes occur.
In a paradigm shift, the team identified a mechanism that involves local amyloid-β-mediated protein translation of tau in the cell body and in the dendrites (small processes), and interestingly, fyn - again - had a major role in this process. Not only did their data present a more cogent mechanism of tau aggregation in disease (than what was previously believed to be the mechanism), but they highlighted neuronal fyn as a drug target, given that this enzyme integrates signal transduction pathways, which lead to the somatodendritic accumulation of tau in Alzheimer's disease.
In a follow-up study, using innovative tools and techniques such as non-canonical amino acids and click chemistry, the team revealed that in primary tauopathies (frontotemporal dementia), different from Alzheimer’s disease, tau actually impairs new protein synthesis, in part because tau causes reduced levels of ribosomal proteins. This work is adding to an extensive body of work by Professor Götz and his team to understand how tau impairs neuronal functions (work ranging from exosomal release mechanisms to synaptic pruning and mitochondrial functions).
Scanning ultrasound is a noninvasive treatment modality for Alzheimer’s disease
(ScienceTranslMed 2015; Brain 2017; Theranostics 2018/2019, Alz Res Ther 2021, Mol Psych 2021)
In a major discovery, Professor Götz’s team developed a non-pharmacological approach for removing oligomeric and fibrillar forms of proteins such as amyloid-β and tau and restoring memory functions in transgenic mouse models. This was achieved by combining intravenously injected microbubbles with repeated scanning ultrasound (SUS) treatments of the brain, causing transient opening of the blood-brain barrier and the entering of blood-borne factors that (in the absence of any drug treatment) activated resident microglia. These internalised amyloid-β into their lysosomes. Amyloid plaque burden was massively reduced and SUSed mice displayed restored memory functions in three complementary tests. Given that repeated SUSing is non-invasive and caused no overt damage to brain tissue, Professor Götz’s study highlights its therapeutic potential for Alzheimer's disease, and possibly other diseases involving protein aggregation.
Professor Götz and his team then showed that SUS can also reduce an intraneuronal tau pathology (Brain 2017), by activating neuronal autophagy (Theranostics 2019). Importantly, SUS also facilitated a more than10-fold uptake of anti-tau antibody fragments not only by the brain but also by neurons. Similarly, the uptake of an Aducanumab analogue – an anti-amyloid- β drug - was greatly facilitated by SUS (AlzResTher 2021). Considering the high anticipated cost of potential Alzheimer’s vaccines (costs for Aducanumab may be in the order of 60,000 US$ per patient per year), this study highlights the possibility of facilitating brain uptake of therapeutic antibodies and thereby reducing costs significantly.
In translating rodent studies to the human brain, the presence of a thick cancellous skull that both absorbs and distorts ultrasound presents a challenge. Götz and his team established sheep as a larger animal model that is more similar to humans, demonstrating safe blood-brain barrier opening (Theranostics 2018). Moreover, the team showed, that SUS with and without microbubbles (i.e. with and without openeing of the blood-brain barrier) can restore the induction of long-term potentiation (LTP), an electrophysiological correlate of memory, as well as spatial memory (MolPsych 2021) indicating the general suitability of the technology for restoring cognition.
Currently, Professor Götz and his team are working together with engineers, clinicians, a CRO, and a commercialisation team to develop a medical device, conduct clinical trials and establish an ultrasound-based ecosystem.