Meet the team

Marc Aurel Busche

"Our central goal is to deepen our understanding of the molecular, cellular and circuit mechanisms that result in memory loss and cognitive decline in Alzheimer’s disease, and to develop targeted treatments to halt disease progression and improve clinical symptoms." Marc Aurel Busche
UK DRI Group Leader

Dr Marc Aurel Busche’s research group studies brain ageing and dementia with a focus on the cellular and neural circuit mechanisms of Alzheimer’s Disease (AD), the most common cause of dementia in elderly people. Marc was among the first to employ high-resolution multiphoton imaging to reveal the earliest functional cellular changes in the amyloid beta plaque (Aβ)-bearing brain in vivo, and he identified a key role for abnormal neuronal hyperexcitability in AD that has inspired a number of ongoing clinical trials. Ongoing work in his laboratory employs advanced imaging, electrophysiological and analytical approaches to characterise the mechanisms underlying progressive cellular and circuit deterioration in AD, with the aim of identifying novel preventative and therapeutic targets. His work has earned him several accolades, including a prestigious Future Leaders Fellowship from UKRI. In addition to his commitment to research, he is an honorary consultant psychiatrist at Queen Square National Hospital for Neurology and Neurosurgery and sees patients approximately once a week.

1. At a glance

Cells and circuits in Alzheimer’s disease and dementia

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that affects millions of people around the world. The disease is neuropathologically characterised by widespread accumulation of abnormal protein aggregates in the brain, namely amyloid beta (Aβ) plaques and tau neurofibrillary tangles. There has been a great deal of research dedicated to elucidating the molecular and genetic underpinnings of AD, however, how pathological alterations in these microscale processes ultimately manifest as changes in cognition and behaviour remains unclear.

To address this critical research gap, Marc’s laboratory’s research converges at the level of neuronal circuits, which act as mediators and modulators of microscopic and macroscopic ‘real-world’ processes, and can be interrogated and manipulated using sophisticated multi-modal techniques. Specifically, the laboratory examines how AD-related peptides impact on individual brain cells and the neuronal circuits in which they are embedded, leading to disease progression and alterations in brain function, cognition, and behaviour. His group is particularly interested in the pathological changes that take place at the earliest stages of AD, prior to the emergence of symptoms, since this may represent the best therapeutic window for effective intervention.

In order to meet that challenge, Marc and his team employ a suite of advanced in vivo and in vitro methods, including multiphoton microscopy, patch-clamp electrophysiology, Neuropixels multi-channel recordings, optogenetics, and wide-field calcium imaging in combination with molecular and cell biological techniques. This enables fine-scale functional mapping of brain circuits and their constituent brain cells to further understand the spatiotemporal effects of AD-related peptides in the brain.

2. Scientific goals

Previously, Marc and colleagues have discovered that nerve cells near to amyloid beta (Aβ)plaques become hyperactive at early stages of AD. This hyperactivity is caused by soluble oligomeric species of Aβ that surround plaques and is causally linked to impaired network oscillations (slow waves) during sleep, leading to learning and memory deficits. Moreover, Aβ-dependent neuronal hyperactivity has been associated with epileptiform activity, as well as epileptic seizures, which may affect up to 40% or more of individuals with AD and has been linked to a more severe clinical presentation. This suggests that modulating and blocking the action of soluble Aβ may be a valuable therapeutic target.

In his more recent work, Marc’s research has extended to the other main protein pathology found in AD, tau neurofibrillary tangles, and specifically the interaction between tau and Aβ. This work has reinforced mounting evidence that Aβ and tau conspire to impair brain function, and that tau-mediated neuronal dysfunction may predominate at later stages of AD. Marc’s laboratory continues to investigate how Aβ and tau interact in order to find novel ways of blocking Aβ/tau synergy therapeutically.

Main objectives and research goals:

1. To understand how genetic and molecular risk factors and changes are linked to cellular and circuit alterations, ultimately leading to cognitive and behavioural decline in AD.

2. To identify therapeutic strategies that block the progressive cellular and circuit changes that are causal for AD dementia.

3. Team members

Dr Samuel S Harris (Research Fellow)
Dr Robert Ellingford (Research Fellow)
Dr Byung Il Lee (Postdoctoral Researcher)
Dr Debanjan Dasgupta (Postdoctoral Researcher)
Dr Jana Hartmann (Postdoctoral Researcher)
Dr Mengke Yang (Postdoctoral Researcher)
Dr Rikesh Rajani (Postdoctoral Researcher) - shared with Dr Carlo Sala Frigerio
Mariam Hellmuth (Visiting Research Student)
Marten Kehring (Visiting Research Student)
Robert Kilzer (Visiting Research Student)
Jana Zunkler (Visiting Research Student)
Francesca Lam (PhD Student)

4. Collaborations

Within UK DRI:

  • Dr Carlo Sala Frigerio, UK DRI at UCL
  • Prof Paul Whiting, UK DRI at UCL
  • Prof Giampietro Schiavo, UK DRI at UCL

Beyond UK DRI:

  • Prof Fred Wolf, Goettingen
  • Prof Bradley Hyman, Boston
  • Prof Kenneth Harris, UCL
  • Prof Matteo Carandini, UCL
  • Dr Selina Wray, UCL
  • Prof Israel Nelken, Jerusalem

5. Topics

Alzheimer’s disease, brain circuits and networks, sleep, tau, amyloid beta

6. Techniques

Multiphoton microscopy, electrophysiology, optogenetics, wide-field calcium imaging, light-sheet microscopy

7. Key publications

Peptide-dependent dysregulation of neural circuit dynamics in Alzheimer’s Disease. Neuron, doi:

Busche, M.A., 2019. Tau suppresses neuronal activity in vivo, even before tangles form. Brain, 142(4), pp.843-846.

Busche, M.A., Wegmann, S., Dujardin, S., Commins, C., Schiantarelli, J., Klickstein, N., Kamath, T.V., Carlson, G.A., Nelken, I. and Hyman, B.T., 2019. Tau impairs neural circuits, dominating amyloid-β effects, in Alzheimer models in vivo. Nature neuroscience, 30(40), p.50.

Busche, M.A., Grienberger, C., Keskin, A.D., Song, B., Neumann, U., Staufenbiel, M., Förstl, H. and Konnerth, A., 2015. Decreased amyloid-β and increased neuronal hyperactivity by immunotherapy in Alzheimer's models. Nature neuroscience, 18(12), p.1725.

Busche, M.A., Kekuš, M., Adelsberger, H., Noda, T., Förstl, H., Nelken, I. and Konnerth, A., 2015. Rescue of long-range circuit dysfunction in Alzheimer's disease models. Nature neuroscience, 18(11), p.1623.

Busche, M.A., Eichhoff, G., Adelsberger, H., Abramowski, D., Wiederhold, K.H., Haass, C., Staufenbiel, M., Konnerth, A. and Garaschuk, O., 2008. Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer's disease. Science, 321(5896), pp.1686-1689.

8. Lab website

Founding funders

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