Synaptic plasticity is the process by which synapses alter their efficiency and this is considered a fundamental property in information processing and storage in the brain.
One prominent model for activity-dependent synaptic plasticity is the NMDA receptor dependent LTP and LTD, which is mainly studied at hippocampal Schaffer collateral CA3-CA1 synapses.
The hippocampus plays a central role in some forms of learning and memory, and has been implicated in a number of neurological and psychiatric disorders, including epilepsy, Alzheimer’s disease (AD) and schizophrenia.
|NGF rescues hippocampal LTP deficit in APP-null mice.
LTP deficits might provide a useful tool for evaluating the efficacy of disease-modifying compounds in the treatment of neurodegenerative diseases
|From brain function
to molecular players
In the past years, the identification of genetic mutations linked to familial AD made it possible to generate transgenic animal models of AD.
These models provide excellent opportunity to examine the bases for the spatial/temporal evolution of the disease and to test the efficacy of novel disease-modifying compounds.
In previous experiments we have shown that in the APP23 mouse model of AD by challenging these animals with learning stimuli there was a deterioration of LTP in hippocampal neurons that was associated with alterations of dendritic spine density.
We are currently employing a wide range of techniques - biochemical, electrophysiological, and behavioural – to target synaptic dysfunction in the hippocampus of transgenic models of AD so to validate new treatments addressed to alleviate the main molecular and functional deficits linked to AD.
Specifically, we have recently demonstrated that AD mice treated with oral γ-secretase modulator CHF5074 show a significant improvement in synaptic plasticity and this effect is correlated with a reduction in intraneuronal Aβ and hyperphosphorylated tau, without change in soluble or oligomeric Aβ levels.
This study provides evidence that early pharmacological intervention can prevent cognitive impairment in preclinical models of AD.
Currently, we are investigating the potential neuroprotective effects of NGF and NGF-analogs to reverse memory deterioration in mice with cognitive impairment.