Tau protein, tauopathies and Alzheimer's disease (AD)
Our research group studies the molecular and cellular biology of neurodegenerative diseases such as Alzheimer’s Disease (AD) and other tauopathies linked with abnormal metabolism of tau protein.
Two lines of research are presently under way:
1. Investigation of the action mechanism(s) of 12A12-mediated neuroprotective action in murine AD strains
Previous studies carried out by our research group have shown that Nerve Growth Factor (NGF) exerts its trophic action by keeping under control in its target cells the endogenous apoptotic cell death, whose improper activation may trigger Alzheimer’s Disease (AD) and other neurodegenerative diseases.
Further in vitro and in vivo experimental evidence have allowed us to identify a crucial connection between the apoptotic events and the pathological alterations of tau protein metabolism with both “loss-of-function” in control of axonal microtubules and “gain of function” due to cleavage at the N-terminal domain and generation of a 20-22 kDa fragment.
This tau-derived peptide is detectable in cellular and animal AD models as well as in hippocampal synapses of affected subjects where it exerts a potent toxic action at the level of local mitochondria. More recently, we have developed a monoclonal antibody -named 12A12mAb- which in vivo selectively neutralizes this harmful specie(s) without altering the full-length normal tau, a neuronal protein involved in many important intracellular functions such as axonal transport. 12A12mAb, when systemically-injected into transgenic AD animals (Tg2576; 3XTg mice), markedly alleviates the disease-associated signs, such as behavioral deficits (spatial memory and orientation) and anatomo-pathological lesions (senile plaques and neuro fibrillary aggregates). At present, we are carrying out experimental studies to clarify the mechanism(s) of action of 12A12mAb for future therapeutic applications.
2. Production of a “humanized" version of 12A12 for clinical studies on human patients suffering from AD
Since our preclinical studies on anti-tau 12A12mAb can offer new opportunities for therapeutic treatment of AD, and possibly of other human neurodegenerative tauopathies, we are developing a “humanized” version of the antibody for the clinical application in patients affected by these devastating disorders.