Research Focus
It remains unclear why some older adults develop memory and learning impairments in neurodegenerative diseases such as Alzheimer’s and Parkinson’s, while others retain cognitive function despite similar brain pathology. Increasing evidence suggests that this variability may be driven by the selective vulnerability of specific brain regions and distinct neuronal and glial cell populations.
Our lab investigates the functional mechanisms underlying cognitive decline, with a focus on vulnerable brain regions such as the hippocampus and prefrontal cortex. We combine ex vivo electrophysiology, including patch-clamp recordings, circuit analysis, and measurements of neuronal oscillations and synaptic plasticity, with advanced imaging, transcriptomics, and proteomics. This integrative approach allows us to link molecular changes to alterations in neuronal and network function.
Neuron–microglia interplay in early Alzheimer’s disease (AD)
Our research has revealed that microglia (the brain’s resident immune cells) play a key role in the early stages of Alzheimer’s disease. We identified a critical transition phase in which changes in microglial state closely coincide with emerging disruptions in hippocampal network activity and function (Pizzirusso et al., 2024). These findings highlight neuroinflammation as an early driver of circuit dysfunction and cognitive decline, suggesting that targeting microglial responses could open new opportunities for early intervention. Building on this work, we are now investigating the precise cellular and molecular mechanisms that link microglial alterations to neuronal dysfunction.
AD and iNPH, multimodal approach to investigate early pathology mechanisms
Idiopathic normal pressure hydrocephalus (iNPH) is a neurological condition characterized by the accumulation of cerebrospinal fluid (CSF) in the brain's ventricles that maintains normal pressure and affects people after 65 years of age. As part of their treatment, these patients undergo shunt brain surgery, which consists of opening a small window in the brain to drain excess CSF. This allows us to obtain live brain tissue, CSF, and blood from the same patient to perform functional experiments in humans. Additionally, 70% of these patients show AD-related pathology in the brain. With these unique samples, we investigate the link between AD pathology and neuronal function and their potential for biomarker discovery.
Using chemogenetics, optogenetics, and pharmacological approaches, we investigate whether microglia could prevent or restore the functional impairments found in mouse models of AD-related pathology in early stages of the disease.
