Cellular and circuit mechanisms of Alzheimer's disease
Lead Research Organisation:
University College London
Department Name: Institute of Neurology
Abstract
Alzheimer's disease (AD) is a ticking time bomb for our society and health care system with populations aging and predictions of over 1 million people affected in the UK by 2025. The overarching aim of this proposal is to understand why neurons and brain circuits become dysfunctional in AD, resulting in devastating impairments of memory and other cognitive abilities. Genetic studies clearly implicate amyloid-beta (Abeta) as a driving force of the disease. However, in sharp contrast to mice that are a model of AD because they overexpress a causative gene (e.g., mutant amyloid precursor protein), blocking or removing Abeta failed in dozens of large-scale clinical trials, involving in total tens of thousands of patients. Perhaps the most obvious difference between the mouse models and Alzheimer patients is the presence of tau-containing neurofibrillary tangles in Alzheimer brains. Importantly, every Alzheimer patient has tau and Abeta. However, the impact of tau on neural circuit function, and the complex interactions among tau and Abeta, are largely unknown. Here I propose to perform cutting-edge cell-type, -layer and brain region-specific in vivo deep two-photon calcium imaging of large neuronal populations to test the hypothesis that tau - but not necessarily neurofibrillary tangles - impairs neuronal activities in neocortex and hippocampus, and that there is synergy between tau and Abeta, accelerating and worsening the impairments. I will 1) determine the specific type of tau causing impaired neuronal function, and identify the underlying mechanisms, 2) determine the mechanisms of the synergistic effects among tau and Abeta in the context of an intact nervous system, and 3) determine the consequences of the cell-specific impairments for long-range brain circuit activities including sleep-related slow-wave oscillations. If, as I propose, neural system impairments in Alzheimer patients start out dependent on Abeta, but become increasingly less so as tau accumulates in the brain, it follows that anti-Abeta treatments would be effective only during the initial Abeta-dependent phase, and help explain the multiple failures of clinical trials of anti-Abeta agents given later in the disease. Mapping the timing and mechanisms of these phases would have crucial importance in informing the next generation of clinical trials; furthermore the highly mechanistic experiments proposed here might reveal novel cellular and synaptic targets for effective therapeutic interventions even beyond Abeta and tau, which is a critical unmet clinical need.
Planned Impact
Impact through innovation/novelty:
There are many potential beneficiaries of this research program. The principal beneficiaries will be national and international academic and industry researchers working on the mechanisms, diagnosis and treatment of Alzheimer's disease. The overarching goal of the proposal is to address two major mysteries in Alzheimer's neurobiology: 1) What is the disease-specific neuronal damage? 2) What is the relationship of amyloid plaques and tau neurofibrillary tangles? We will provide new data related to these questions and this will enable researchers in the field to apply that knowledge, generate new hypothesis and help inform diagnostic and therapeutic approaches as well as clinical trials. This would also benefit many Alzheimer patients, their families, and the health service and the wider population upon which much of the economic burden falls.
Impact for UK Dementia Research Institute:
The expertise and knowledge acquired through the proposed research project will greatly benefit the UK Dementia Research Institute whose mission is to understand the biological mechanisms underpinning dementia. A large number of researchers from the institute may take advantage of the presence of a cutting-edge in vivo two-photon imaging platform developed during the Fellowship. Importantly, all methods will be made available to all researchers in the institute and will be open to collaborations.
Drug discovery companies
Industry benefits because the proposed experiments directly inform clinical trials and help 'failure analysis' of the numerous failed amyloid based trials. In addition, the research will advance our understanding of the basic processes underlying disease mechanisms and might uncover novel treatment targets beyond amyloid and tau, a critical unmet clinical need. Finally, the companies will in the long run benefit from the technology developed during the fellowship, as many problems of interest including the specific cell types involved in the disease can be readily studied using the proposed in vivo imaging platform.
Impact for Society:
Alzheimer's disease currently afflicts 850,000 people in the UK, costing the health care system billions. By understanding why neurons become dysfunctional in the disease, we will be able to inform clinical approaches, accelerating the development of successful treatments. The proposed research will also help to understand the recent failures of numerous amyloid based clinical trials which is of critical importance for public health, for therapeutic development, and for the many patients with Alzheimer's disease who continue to suffer without effective therapies. In case the proposed research leads to a novel treatment, the resulting reductions in morbidity and mortality (dementia is the leading cause of death in the UK) will benefit health and the economy.
There are many potential beneficiaries of this research program. The principal beneficiaries will be national and international academic and industry researchers working on the mechanisms, diagnosis and treatment of Alzheimer's disease. The overarching goal of the proposal is to address two major mysteries in Alzheimer's neurobiology: 1) What is the disease-specific neuronal damage? 2) What is the relationship of amyloid plaques and tau neurofibrillary tangles? We will provide new data related to these questions and this will enable researchers in the field to apply that knowledge, generate new hypothesis and help inform diagnostic and therapeutic approaches as well as clinical trials. This would also benefit many Alzheimer patients, their families, and the health service and the wider population upon which much of the economic burden falls.
Impact for UK Dementia Research Institute:
The expertise and knowledge acquired through the proposed research project will greatly benefit the UK Dementia Research Institute whose mission is to understand the biological mechanisms underpinning dementia. A large number of researchers from the institute may take advantage of the presence of a cutting-edge in vivo two-photon imaging platform developed during the Fellowship. Importantly, all methods will be made available to all researchers in the institute and will be open to collaborations.
Drug discovery companies
Industry benefits because the proposed experiments directly inform clinical trials and help 'failure analysis' of the numerous failed amyloid based trials. In addition, the research will advance our understanding of the basic processes underlying disease mechanisms and might uncover novel treatment targets beyond amyloid and tau, a critical unmet clinical need. Finally, the companies will in the long run benefit from the technology developed during the fellowship, as many problems of interest including the specific cell types involved in the disease can be readily studied using the proposed in vivo imaging platform.
Impact for Society:
Alzheimer's disease currently afflicts 850,000 people in the UK, costing the health care system billions. By understanding why neurons become dysfunctional in the disease, we will be able to inform clinical approaches, accelerating the development of successful treatments. The proposed research will also help to understand the recent failures of numerous amyloid based clinical trials which is of critical importance for public health, for therapeutic development, and for the many patients with Alzheimer's disease who continue to suffer without effective therapies. In case the proposed research leads to a novel treatment, the resulting reductions in morbidity and mortality (dementia is the leading cause of death in the UK) will benefit health and the economy.
Organisations
- University College London (Fellow, Lead Research Organisation)
- Max Planck Society (Collaboration)
- Heidelberg University (Collaboration)
- Wellcome Trust (Collaboration)
- Massachusetts General Hospital (Collaboration)
- German Centre for Neurodegenerative Diseases (Collaboration)
- Medical Research Council (MRC) (Collaboration)
- IMPERIAL COLLEGE LONDON (Collaboration)
Publications
Busche MA
(2020)
Synergy between amyloid-ß and tau in Alzheimer's disease.
in Nature neuroscience
Harris SS
(2020)
Tipping the Scales: Peptide-Dependent Dysregulation of Neural Circuit Dynamics in Alzheimer's Disease.
in Neuron
Harris SS
(2021)
The Reciprocal Interaction Between Sleep and Alzheimer's Disease.
in Advances in experimental medicine and biology
Maestú F
(2021)
Neuronal excitation/inhibition imbalance: core element of a translational perspective on Alzheimer pathophysiology
in Ageing Research Reviews
Mensch M
(2021)
A?-a and A?-ß peptides impair LTP ex vivo within the low nanomolar range and impact neuronal activity in vivo.
in Alzheimer's research & therapy
Milioto C
(2024)
PolyGR and polyPR knock-in mice reveal a conserved neuroprotective extracellular matrix signature in C9orf72 ALS/FTD neurons
in Nature Neuroscience
Ong-Pålsson E
(2022)
The ß-Secretase Substrate Seizure 6-Like Protein (SEZ6L) Controls Motor Functions in Mice.
in Molecular neurobiology
Pigoni M
(2020)
Seizure protein 6 controls glycosylation and trafficking of kainate receptor subunits GluK2 and GluK3.
in The EMBO journal
Description | 1) I have published two high impact papers that draw increased attention to the importance of brain circuit dysfunction in Alzheimer's Disease for diagnostic, prognostic and therapeutic approaches (Busche and Hyman 2020, Nature Neuroscience; Harris et al. 2020, Neuron) 2) I have co-authored papers that identified an important physiological function of a protein called seizure-6, which is implicated in Alzheimer's Disease and other neuropsychiatric disorders (Pigoni et al 2020, EMBO J; Ong-Pålsson et al 2022, Mol Neurobiol) |
Exploitation Route | The above outputs are significant because they help explain recent failures of clinical trials in Alzheimer's Disease and inform the next generation of clinical trials, thereby accelerating a cure for this devastating disease. |
Sectors | Education Healthcare Pharmaceuticals and Medical Biotechnology |
Description | 3D patient-derived organoids: A viable and complementary model to study neural system dysfunction in Alzheimer's Disease |
Amount | £90,000 (GBP) |
Funding ID | NC/W001675/1 |
Organisation | National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) |
Sector | Public |
Country | United Kingdom |
Start | 02/2022 |
End | 10/2025 |
Description | Cellular and circuit mechanisms linking traumatic brain injury and dementia |
Amount | £249,699 (GBP) |
Organisation | UK Dementia Research Institute |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2022 |
End | 10/2025 |
Description | Cellular and circuit mechanisms of Alzheimer's disease |
Amount | £575,668 (GBP) |
Funding ID | MR/X011038/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 04/2023 |
End | 04/2026 |
Description | Eisai/UK DRI Research Programme |
Amount | £249,322 (GBP) |
Organisation | UK Dementia Research Institute |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2020 |
End | 03/2022 |
Description | Neural replay - a novel functional biomarker of latent Alzheimer's Disease |
Amount | £169,029,541 (GBP) |
Organisation | UK Dementia Research Institute |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 06/2023 |
End | 06/2026 |
Description | Roche Postdoctoral Programme |
Amount | £227,700 (GBP) |
Organisation | Roche Pharmaceuticals |
Sector | Private |
Country | Global |
Start | 02/2021 |
End | 01/2023 |
Description | Scaling the divide in Alzheimer's Disease: An integrated molecular, cellular and network-level study |
Amount | $191,623 (USD) |
Organisation | Cure Alzheimer’s Fund |
Sector | Charity/Non Profit |
Country | United States |
Start | 03/2024 |
End | 02/2025 |
Title | Deep-tissue two-photon microscope |
Description | Installation of a deep-tissue two-photon imaging set-up for in vivo and in vitro recordings of brain activity |
Type Of Material | Technology assay or reagent |
Year Produced | 2019 |
Provided To Others? | No |
Impact | Facilitates a new research direction in my lab |
Title | Large field of view two-photon mesoscope |
Description | This is a specialised two-photon microscope that enables large field of view recordings from multiple brain regions in mice in vivo. Similar instruments are available only in very few labs around the world. |
Type Of Material | Technology assay or reagent |
Year Produced | 2020 |
Provided To Others? | Yes |
Impact | Instrument just established, no impact yet |
Title | MesoSPIM Lightsheet microscope |
Description | This is a custom-built, open-hardware and open-software lightsheet microscope |
Type Of Material | Technology assay or reagent |
Year Produced | 2020 |
Provided To Others? | Yes |
Impact | The instrument has attracted collaborations with researchers from DRI and across UCL including the Institute for Cancer Research and the UCL Kidney Development & Disease Research Group |
URL | http://mesospim.org |
Title | Neuropixels electrophysiology |
Description | Neuropixels are next-generation silicon probes with unprecedented capabilities. With 960 densely-spaced sites on a 10 mm long shank, they enable simultaneous recording of the activity of hundreds of neurons across multiple areas of the mouse brain, which my laboratory is using to compare function between relevant mouse models of neurodegeneration. |
Type Of Material | Technology assay or reagent |
Year Produced | 2017 |
Provided To Others? | Yes |
Impact | Neuropixels are increasingly used by multiple labs and have already led to significant new insights into how the brain works in health and disease. |
Description | Computational models of Alzheimer's Disease progression |
Organisation | Max Planck Society |
Department | Max Planck Institute for Experimental Medicine |
Country | Germany |
Sector | Academic/University |
PI Contribution | Intellectual and data exchange |
Collaborator Contribution | Data analysis and intellectual exchange |
Impact | First paper published in Neuron: Harris SS, Wolf F, De Strooper B, Busche MA. Tipping the Scales: Peptide- Dependent Dysregulation of Neural Circuit Dynamics in Alzheimer's Disease. Neuron. 2020 Aug 5;107(3):417-435. doi: 10.1016/j.neuron.2020.06.005. Epub 2020 Jun 23. PMID: 32579881. |
Start Year | 2020 |
Description | In vivo investigations of novel Alzheimer models |
Organisation | German Centre for Neurodegenerative Diseases |
Country | Germany |
Sector | Public |
PI Contribution | Investigations on protein-function relationships in novel models of Alzheimer's Disease |
Collaborator Contribution | Expertise in mouse models and protein biochemistry |
Impact | No outcomes yet |
Start Year | 2022 |
Description | Link between traumatic brain injury and dementia |
Organisation | Imperial College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Provide expertise on Alzheimer's Disease |
Collaborator Contribution | Provide expertise on Traumatic Brain Injury |
Impact | No outputs yet |
Start Year | 2022 |
Description | Neurophysiological markers of early Alzheimer's Disease |
Organisation | Medical Research Council (MRC) |
Department | MRC Brain Network Dynamics Unit at the University of Oxford (BNDU) |
Country | United Kingdom |
Sector | Public |
PI Contribution | We provide expertise related to Alzheimer's Disease to a collaborative project |
Collaborator Contribution | They provide expertise in human magnetoencephalography (Wellcome) and hippocampal neuronal physiology (Oxford) to a collaborative project |
Impact | Succesful UK DRI Grand Challenge Award |
Start Year | 2022 |
Description | Neurophysiological markers of early Alzheimer's Disease |
Organisation | Wellcome Trust |
Department | Wellcome Trust Cente for Neuroimaging |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We provide expertise related to Alzheimer's Disease to a collaborative project |
Collaborator Contribution | They provide expertise in human magnetoencephalography (Wellcome) and hippocampal neuronal physiology (Oxford) to a collaborative project |
Impact | Succesful UK DRI Grand Challenge Award |
Start Year | 2022 |
Description | Physiological functions of APP in the brain |
Organisation | Heidelberg University |
Country | Germany |
Sector | Academic/University |
PI Contribution | In vivo calcium imaging experiments in APP knockout models |
Collaborator Contribution | Biochemical, histopathological and behavioural characterisation of the models. |
Impact | Paper in preparation |
Start Year | 2018 |
Description | Role of Seizure protein 6 in the normal and diseased brain |
Organisation | German Centre for Neurodegenerative Diseases |
Country | Germany |
Sector | Public |
PI Contribution | Performed in vitro electrophysiology experiments |
Collaborator Contribution | Performed biochemical and histopathological analyses |
Impact | Paper published in EMBO Journal: Pigoni M, Hsia HE, Hartmann J, Rudan Njavro J, Shmueli MD, Müller SA, Güner G, Tüshaus J, Kuhn PH, Kumar R, Gao P, Tran ML, Ramazanov B, Blank B, Hipgrave Ederveen AL, Von Blume J, Mulle C, Gunnersen JM, Wuhrer M, Rammes G, Busche MA, Koeglsperger T, Lichtenthaler SF. Seizure protein 6 controls glycosylation and trafficking of kainate receptor subunits GluK2 and GluK3. EMBO J. 2020 Aug 3;39(15):e103457. doi: 10.15252/embj.2019103457. Epub 2020 Jun 22. PMID: 32567721; PMCID: PMC7396870. |
Start Year | 2019 |
Description | Synergy between amyloid-beta and tau in Alzheimer's Disease |
Organisation | Massachusetts General Hospital |
Country | United States |
Sector | Hospitals |
PI Contribution | Experimental and intellectual contributions |
Collaborator Contribution | Material and intellectual contributions |
Impact | Paper published in Nature Neuroscience: Busche MA, Hyman BT. Synergy between amyloid-ß and tau in Alzheimer's disease. Nat Neurosci. 2020 Oct;23(10):1183-1193. doi: 10.1038/s41593-020-0687-6. Epub 2020 Aug 10. PMID: 32778792. |
Start Year | 2019 |
Description | BBC interview |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | BBC interview on research in Alzheimer's Disease |
Year(s) Of Engagement Activity | 2019 |
Description | Building an early warning system for dementia - A public webinar from the UK DRI |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | In this special UK DRI "meet the researchers" public webinar, organised with our charity founders Alzheimer's Society and Alzheimer's Research UK, we have explore what an early warning system for dementia could look like. We have heard from researchers working to develop a simple blood test for Alzheimer's, found out how technology in our home can help detect changes in our behaviour and learnt more about how better understanding of our genetics could identify those most at risk. |
Year(s) Of Engagement Activity | 2021 |
Description | Fundraising visit to my lab by potential donors of the Alzheimer Society |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Supporters |
Results and Impact | I showed my lab to potential donors of the Alzheimer's Society. |
Year(s) Of Engagement Activity | 2019 |
Description | Interview for Knowable Magazine |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Interview by Knowable Magazine about my research and Alzheimer's Disease in general |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.knowablemagazine.org/article/health-disease/2019/watching-alzheimers-action |
Description | Interview/comment for national news |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Gave a comment/interview to several German newspapers about recent research in Alzheimer's Disease |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.sciencemediacenter.de/alle-angebote/research-in-context/details/news/genmutation-schuetz... |