 |
 |
|
| Cláudia Fragão Pereira |
| Group Leader |
Associate Researcher
Institute of Biochemistry
Faculty of Medicine
University of Coimbra
Portugal |
|
 |
|
Ph. |
+351 239 820190 |
| Fax |
+ 351 239 822776 |
|
|
|
|
 |
|
|
| Aim of the group |
The amyloid-beta (Aβ), alpha-synuclein (α-syn) and prion (PrPSc isoform) peptides are now considered crucial in the pathogenesis of Alzheimer’s, Parkinson’s and Prion’s diseases, respectively, which are characterized by synaptic and neuronal loss. Although the aberrant peptide accumulation is recognized as an important common feature in these neurodegenerative disorders, the underlying disease mechanisms remain an important subject of competing hypothesis and debate.
The aim of the Group “Molecular Mechanisms of Disease” is to investigate the primary molecular and cellular pathogenic mechanisms underlying neuronal injury and death during aging, the major risk factor for several neurodegenerative disorders, and that triggered by the amyloidogenic peptides associated with Alzheimer’s, Parkinson’s and Prion’s diseases, and to identify and test novel neuroprotective and neurorepair strategies. |
|
 |
|
| Research Highlights |
We described for the first time that a functional mitochondria is required for Aβ- or PrP-induced apoptosis in studies conducted in mitochondrial DNA-depleted rho0 cells. In cultured cortical neurons, we established that these amyloidogenic peptides activate the mitochondria-mediated apoptotic cell death pathway. In addition, Cdk5 was found to be activated in Aβ- or PrP-treated neurons leading to apoptotic death as a consequence of an abortive cell cycle reactivation.
We provided evidence that mitochondria are a fundamental link between age-related pathologies, diabetes and AD. Brain mitochondria isolated from diabetic rats present increased susceptibility to Aβ injury and mitochondrial dysfunction is potentiated in older animals. Data obtained with cultured fibroblasts and human brain tissue corroborates the existence of an age-related mitochondrial impairment that is more pronounced in AD and is associated with increased degradation of these organelles by autophagy. The role of mitochondrial dysfunction in AD was further explored using cybrid cells that were demonstrated to have a compromised ability to cope with toxic insults, in particular with Aβ-induced ER stress.
One of the major interests of the group concerns the investigation of endoplasmic reticulum (ER)/mitochondria cross-talk as a primary molecular mechanism leading to synaptic and neuronal loss triggered by Aβ or PrP. In cultured cortical neurons, these peptides increased ER Ca2+ release and activated the ER stress-mediated apoptotic pathway by a mitochondrial-dependent process. As a consequence of ER Ca2+ release, oxidative stress is triggered and the pro-apoptotic protein Bax is translocated to mitochondria leading to cytochrome c release and caspases activation. Using an AD mouse model, the triple transgenic mice (3 x Tg-AD), we showed that oxidative stress is an early event during the progression of the amyloid pathology, occurring before the deposition of Aβ in amyloid plaques and cognitive deficits. We also showed that Aβ oligomers are more toxic than fibrils to cortical neurons, leading to GSK3β-mediated tau phosphorylation and apoptotic death through a mechanism involving ER Ca2+ release. In addition, cdk5, which is indirectly activated by Ca2+, was also involved in tau phosphorylation triggered by Aβ and PrP.
Another focus of research of our group is the role of neuroinflammation, in particular of microglia activation, on Aβ- or PrP-induced neuronal death. Using co-cultures of microglia/cortical neurons challenged with Aβ or PrP, the release of interleukin-6 by activated microglia was observed to enhance neuronal death further supporting a role of neuroinflammation in AD and PRE. Moreover, the compromised glutamate clearance by astrocytes was shown to be involved in the toxicity of Aβ peptide.
Our group also contributed to elucidate the mechanisms underlying cholinergic dysfunction in AD. We have shown that pyruvate depletion due to glycolysis impairment is responsible for the decrement of acetylcholine (ACh) release in cortical neurons treated with Aβ that also downregulates nicotinic ACh receptors and increases the activity of acetylcholinesterase (AChE), through a mechanism that involves oxidative stress. Moreover, our group collaborated in a study that identified a novel form of AChE with 55 kDa in neurons.
We have recently initiated studies addressing the role of mitochondria dysfunction in Parkinson’s disease (PD). Our data indicate that a mitochondrial defect leads to oxidative stress, namely to an increase in protein oxidation, that may compromise proteasomal function. In addition, we provided evidence that mitochondrial impairment causes the loss of microtubule function, culminating in microtubule depolymerization that enhances α-syn aggregation via calpain activation.
|
|
| Further Information and Publications |
|
| back |
|
