Neurodegeneration. Dementia. Alzheimer's Disease. Brain Ageing. Neural Circuits

Brain Ageing and Neurodegeneration

Selective vulnerability of brain circuits in early Alzheimer’s Disease

My group’s research is very translational and directed at improving the lives of people living with Alzheimer’s Disease (AD) and related neurodegenerative diseases. We aim to understand how AD begins and progresses over time, and how the pathology alters the brain circuits that support memory and cognition. These circuit changes emerge before nerve cells are lost, and thus provide a window of opportunity to prevent the onset of memory and cognitive decline. To study this, we pioneer novel brain-wide, cellular-resolution, in vivo imaging and electrophysiological approaches, and seek to unravel the effects of pathology on circuit function across different timescales, brain regions, and cell types, and assess how impaired circuit activity relates to memory and cognitive impairment. We aim to translate our research from bench to bedside by identifying sensitive and dynamic physiological markers of disease in intact patients, and through pioneering rational circuit-based treatment approaches for the clinic. We previously established neuronal hyperactivity as an early, Aβ-dependent and reversible determinant of early brain circuit dysfunction in AD. In cortex, we discovered clusters of hyperactive neurons concentrated around Aβ plaques, due to impaired synaptic inhibition. In hippocampus, hyperactivity emerges before plaque deposition and is caused by soluble Aβ; lowering soluble Aβ normalises activity in vivo, and exogenous soluble Aβ is sufficient to promote hyperactivity. At the brain‑wide level, Aβ disrupts the propagation and long‑range coherence of sleep slow‑wave activity across neocortex, hippocampus and thalamus; enhancement of synaptic inhibition restores coherent dynamics and improves memory. We also identified a selective early vulnerability of deep cortical layers. We found that parvalbumin fast‑spiking interneurons in layers 5 and 6 show reduced spiking and impaired sensory tuning, while superficial layer interneurons remain normal. These deficits coincide with reduced NPTX2 in excitatory neurons, loss of GluA4 in parvalbumin cells, and fewer excitatory synapses onto these interneurons. Restoring NPTX2 rescues spiking. Together, these observations point to an impaired excitation-inhibition balance within brain circuits in early AD. We revealed a completely unexpected non‑neuronal source of pathogenic Aβ in the brain. Oligodendrocytes produce substantial Aβ in human brain, and selective suppression of oligodendrocyte Aβ is sufficient to restore neuronal function and improves Aβ pathology. This result challenges a common assumption about the origin of pathogenic Aβ in the brain and provides a novel therapeutic opportunity. We further showed that tau from the brain’s of people with AD directly suppresses a fundamental coding mode in hippocampus that supports memory-guided cognition. We found that high‑molecular‑weight tau isolated from human AD brain impairs complex‑spike bursting in CA1 neurons, independent of Aβ. These deficit are associated with reduced CaV2.3 R-type calcium channels that support bursting in vivo, indicating a reversible mechanism that could contribute to tau‑related cognitive impairment in AD. We revealed that the amyloid precursor protein (APP) family is not only the source of Aβ but also plays a key physiological role at synapses. In the healthy brain, APP supports spontaneous neuronal activity by sustaining synaptic NMDA receptor function. Deletion of APP family members from excitatory cortical and hippocampal neurons reduces NMDA receptor density, suppresses circuit dynamics, and increases the proportion of silent neurons. These findings point to APP as a synaptic protein that is essential for normal brain function, and suggest that therapeutic strategies targeting this protein family must consider this physiological role. In conclusion, our work reconceptualises AD as a disorder of brain circuit function that emerges early and retains a degree of reversibility before neuronal loss occurs. Soluble Aβ promotes neuronal hyperactivity and disrupts large-scale circuit dynamics. Reduced NPTX2 in excitatory neurons weakens synaptic drive onto parvalbumin interneurons in deep cortical layers, contributing to loss of inhibitory control and increased circuit excitability. High-molecular-weight tau from human brain suppresses hippocampal burst coding through Cav2.3 channels, providing a cellular mechanism that may underlie the strong association between tau and cognitive decline. These findings define distinct but convergent points of failure that are amenable to therapeutic targeting. They broaden the scope of intervention beyond Aβ and tau alone and suggest specific strategies to restore circuit function in vivo. The physiological readouts we define provide a direct translational link to human studies and establish a framework for circuit-based therapies in AD.

Connection to Clinical Practice

I am a psychiatrist specialised in memory and cognitive disorders and Head of the Department of Dementia at the University Hospital of Geriatric Medicine Felix Platter, where I serve as clinical lead for the Memory Clinic and Old Age Psychiatry. My work is guided by a continuous exchange between clinic and laboratory: unmet patient needs inform the research questions we pursue, and mechanistic insights from the lab are are carried forward into the clinic, where they can reach patients. Through this continuous dialogue between clinic and lab we aim to turn fundamental understanding into tangible benefits for those affected by memory and cognitive disorders.