Basic neuroscience and Alzheimer's research

With an increasing life expectancy, the number of Australians suffering from Alzheimer’s disease and related dementias, including frontotemporal dementia, is projected to dramatically increase from 460,000 currently to approximately 1.5 million by 2050.

The Götz laboratory, which forms part of the Clem Jones Centre for Ageing Dementia Research (CJCADR), aims to understand disease initiation and progression at a molecular and cellular level using cellular and animal models, and to develop novel therapies. Inevitably, we are applying the tools we are developing to also understand fundamental mechanisms of memory or the physiological role of proteins implicated in disease. In recent years, a major focus for the group is in developing therapeutic ultrasound into a treatment modality for human disease.

CJCADR Dementia Forum - at home edition 2020

Group leader

Professor Jürgen Götz

Professor Jürgen Götz

Group Leader, Basic neuroscience and Alzheimer's research

Director, Clem Jones Centre for Ageing Dementia Research

  +61 7 334 66300
  j.goetz@uq.edu.au
  UQ Researcher Profile

To develop a cure for Alzheimer’s disease and to develop a system that overcomes the blood-brain barrier as a major hurdle in drug delivery.

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, Götz is recognized as a key opinion leader – he is currently working on his 8th major review for the highly cited and regarded Nature Reviews series.

 

(A) Interaction of β-amyloid and tau in Alzheimer's disease - Proving the amyloid cascade hypothesis (Science 2001)

A century ago, Alois Alzheimer, in his landmark discovery, described plaques and tangles as the hallmark lesions of a disease that would eventually be named after him. However, it was only in the early 1980s that the amyloid-β (Aβ) peptide was identified as the principal component of amyloid plaques, with tau being the principal tangle component.

How Aβ and tau interact is an important question in the field, with the amyloid cascade hypothesis developed in the 1990s, placing Aβ upstream of tau in a pathocascade. In a breakthrough research achievement, Götz proved that Aβ is indeed upstream of tau and causes the latter to aggregate into filaments. This major advance was made possible by using, for the first time, a combined transgenic and stereotaxic transplantation approach.

This advance was made possible by novel transgenic mouse models of AD, a research field Götz pioneered. He was the first to establish a tau transgenic mouse model to achieve a pre-tangle pathology. From here, Götz established models with a more advanced pathology, which proved that tau aggregation can cause degeneration as evidenced, for example, by Wallerian degeneration. The identification of pathogenic mutations in the MAPT 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 Aβ-mediated tau filament formation.

 

(B) Aβ toxicity is tau-dependent – A paradigm shift in the field (Cell 2010)

Although Götz was able to place tau downstream of A in the ‘amyloid cascade hypothesis’, it was later revealed that the tau protein is no innocent bystander. In a major development, Götz and his team subsequently demonstrated that tau is required for Aβ to exert its neurotoxicity. They showed that the ‘axonal’ protein tau has an additional, previously unrecognised, dendritic function in the post-synaptic targeting of the kinase Fyn, a substrate of which is the NMDA receptor (NMDAR).

The team revealed that the tau-mediated localisation of Fyn is essential to the phenotype of Aβ-plaque-forming APP23 mice. These mice are characterised by memory impairment, increased susceptibility to experimentally induced seizures, and premature mortality. Crossing APP23 mice with tau-/- mice rescued them from the observed deficits. Götz’s team revealed that, remarkably, this rescue occurred in the absence of any changes to Aβ levels, indicating that high Aβ levels alone are insufficient to cause toxicity; instead, tau is needed for Aβ to exert toxicity, by targeting Fyn to the dendrite, where it phosphorylates a subunit of the NMDAR that then recruits PSD-95 to form an excitotoxic signalling complex. They showed in vivo that the targeted uncoupling of the Fyn-mediated interaction of the NMDAR and PSD-95 with the small NMDAR-based peptide Tat-NR2B9c also prevents premature death and memory deficits.

Broad implications of this work are that although the amyloid cascade places tau downstream of Aβ, tau plays an essential role in mediating Aβ toxicity. The NMDAR/PSD-95 and tau/Fyn interactions also 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.

 

(C) Fyn-mediated local protein translation of tau – A more congruent mechanism to explain the somatodendritic accumulation of tau in AD (EMBO J 2017 & 2019)

Götz has a major interest in understanding what drives the accumulation of proteins in an aggregated form as this is the unifying feature of neurodegenerative disorders. Tau, for example, is axonally enriched. However, in AD and related tauopathies, it accumulates in the soma and dendrites in a massively phosphorylated form. It is generally assumed that hyperphosphorylated tau in the axon detaches from the microtubules and then passes through the axon initial segment, which serves as a diffusion barrier, before accumulating in the cell body and dendrites; a process that is partly mediated by Aβ. However, whether Aβ employs a mechanism other than relocalisation of tau to account for the massive accumulation of tau in the somatodendritic compartment remained unclear.

In a paradigm shift, Götz identified a more cogent mechanism that involves local Aβ-mediated protein translation of tau in the somatodendritic domain, induced by oligomeric Aβ and mediated by Fyn that activates the ERK/S6 signalling pathway. He demonstrated activation of this pathway in various cellular systems and animal models. Götz found that both pharmacological inhibition and genetic deletion of Fyn abolished the Aβ-induced tau overexpression via ERK/S6 suppression. Together, these findings present a more cogent mechanism of tau aggregation in disease. Moreover, they highlight neuronal Fyn as a drug target, given that this kinase integrates signal transduction pathways, which lead to the somatodendritic accumulation of tau in AD.

In a second study, using non-canonical amino acids and a click chemistry approach, Götz revealed that in primary tauopathies, different from AD, 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 Götz and his team, how the scaffolding protein tau impairs neuronal functions.

 

(D) Scanning ultrasound removes Aβ as well as tau and restores memory in an Alzheimer's disease mouse model – a new treatment strategy (ScienceTranslMed 2015; Brain 2017; Theranostics 2018/2019)

In a major patented discovery, Götz’s team developed a non-pharmacological approach for removing oligomeric and fibrillar forms of proteins such as Aβ 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 Aβ into their lysosomes. 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, Götz’s study highlights its therapeutic potential for AD, and possibly other diseases involving protein aggregation.

Götz then showed that SUS can also reduce an intraneuronal tau pathology (Brain 2017), by activating neuronal autophagy (Theranostics 2019). Importantly, SUS also facilitated a >10-fold uptake of anti-tau antibody fragments not only by the brain but also by neurons. Considering the high anticipated cost of potential AD vaccines, 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).

Professor Götz and his team are working together with several engineering teams, clinicians, a CRO, and a commercialisation team, supported with >20m$ funds (including MRFF) to develop a medical device, conduct clinical trials and establish an ultrasound-based ecosystem.

  • Role of exosomes in tau spreading
  • Role of tau in protein translation in response to scaling paradigms
  • Tau antibodies – therapeutic potential and target engagement
  • Blood-brain barrier in response to therapeutic ultrasound
  • Super resolution microscopy to understand synaptic dysfunction in Alzheimer’s disease
  • Super resolution microscopy to understand BBB opening in response to therapeutic ultrasound
  • Glial Tyrobp in development and disease
  • Novel Alzheimer’s mouse models using CRISPR gene editing technology
  • Therapeutic ultrasound as a therapy for Alzheimer’s disease
  • Ultrasound as a neuromodulatory tool 

View all publications

         

Our approach

The Götz group is a multidisciplinary, international laboratory with its members being trained in biology or engineering. We use standard cellular, molecular, histological, biochemical and behavioural methods. Other techniques include click chemistry, SWATH proteomics and super resolution microscopy. We further generate our own transgenic mouse models including CRISPR gene-edited mice. The team combine approaches which makes the Götz laboratory an exciting place to work and research. As low frequency ultrasound is still a research area in its infancy, there is a lot for us to discover.

Research areas

  • Pathomechanisms in Alzheimer’s dementia
  • Development of therapeutic anti-tau antibodies
  • Therapeutic ultrasound for drug delivery and neuromodulation (R&D)
  • Any other existing, albeit more peripheral projects

Our team

Group Leader


Pathomechanism team


Ultrasound Team


Antibody Team


Alumni (Australia)

  • Della David
  • Nicole Schonrock
  • Yun-An Lim
  • Lars Ittner
  • Yazi Ke
  • Arne Ittner
  • Milena Ullrich
  • Vanessa Liang
  • Julia Gutmann
  • Yee-Lian Chew (cs)
  • J Bertran-Gonzalez
  • Miriam Matamales
  • Di Xia
  • Sian Baker
  • Robert Hatch
  • Ann van der Jeugd
  • Yan Wei
  • Amandine Grimm
  • Phillip Janowicz
  • Nadia Cummins
  • Chuanzhou (Joe) Li
  • Rucha Pandit
  • David Brici
  • Maryam Odabaee