Targeting Early disease mechanisms in neurodegenerative disorders and the neurobiology of memory capacity

Targeting Early disease mechanisms in neurodegenerative disorders
Neurodegenerative disorders are characterized by progressive neuropathological processes that can last decades before a conspicuous loss of neurons can be detected. Therefore, there is a large therapeutic window to find early subtle behavioural and cognitive symptoms that allow early diagnosis and the discovery of the disease mechanisms leading to neuronal loss. Our group is interested in the identification of these early behavioural and synaptic alterations, through sensitive behavioural tasks for rodents. Using a top-down approach we move from the behavioural defects to the neuronal, biochemical and molecular mechanisms which underlie them, to finally targeting these defects with small molecules and provide proof-of concept pre-clinical evidence of their therapeutic efficacy. Using this top-down research strategy, we are working on:
The identification of early cognitive and emotional deficits in animal models of age-related neurodegenerative disorders (Ageing, Alzheimer’ disease and Parkinson’ disease) focusing on the interaction between glutamate-dopamine transmission and its modulation by autophagy.
The identification of early behavioural and synaptic changes in lysosomal storage disorders with altered signalling of heparan sulfate, focusing on dopamine signalling.
The neurobiology of memory capacity
We are currently investigating a little-explored aspect of memory processes, which is the neurobiology of memory load capacity, i.e., the number of items that a subject can remember for a short time interval, in normal and pathological conditions. We have developed novel behavioural tasks to study MC in rodents and demonstrated that mice have a limited MC of about 6 objects and that high memory load processing requires post-translational modification of glutamate receptors in the hippocampus. We recently showed that MC is impaired in early ageing and can be rescued by autophagy enhancers. Through a combination of behavioural, genetic, pharmacological and molecular approaches we are providing novel insights into (i) the role of specific brain regions and dopamine-regulated molecular pathways in supporting memory load capacity, (ii) disease mechanisms leading to memory capacity dysfunctions in schizophrenia and neurodegenerative disorders and (iii) sex-differences in memory capacity.

The "Total Award" amount indicated for this project represents the share of the funding of the Telethon Foundation for research by the Tigem institute from January 2022 until last budget year, calculated based on the size of the research group.