Dr Pavlos Alifragis

Research interests

 

Alzheimer's disease

The extracellular deposition of amyloid beta (Aβ) is one of the histopathological hallmarks of Alzheimer’s disease (AD). The identification of Aβ as the major component of senile plaques, led initially to the belief that deposition of Aβ, was responsible for neuronal degeneration and cell death in AD patients. Even though this initial hypothesis has been modified, oligomeric forms of Aβ are still considered to be a significant contributor to the progression of AD. It is believed that the presence intracellular Aβ (iAβ) can be a supplementary trigger for defective Synaptic plasticity, neuronal stress (as an early event in AD) is becoming gradually clearer.

In my lab we are interested in the biological effects of Aβ peptides and in identifying innovative ways to develop new therapies:

1) Signaling mechanisms affected by beta amyloid (Aβ) peptide in neurons

We are interested in understanding the mechanisms by which iAβ induces synaptic dysfunction. Initially, a proteomic screen was performed to look into possible interacting partners of Aβ. The preliminary results of my group showed that Aβ interacts with a ubiquitous synaptic vesicle (SV) protein called Synaptophysin (Syp) suggesting a unique and surprising role of Aβ in the physiology of neurons. This interaction is important because we showed that upon internalisation, Aβ is quickly transported to the presynaptic terminus inducing aberrant neurotransmitter release as a result of Aβ disrupting the interaction between Syp and VAMP2 (a SNARE protein). We also showed that further to its interaction with Syp, exposure of neurons to Aβ peptides increases the availability of synaptic vesicles to participate in neurotransmitter release changing the phosphorylation of Synapsin1. What is more interesting we showed that valproic acid can reverse these effects.

We are currently expanding on our results, investigating the effects of Aβ in the phosphorylation of target molecules and also look into how drugs used for treatment of early symptoms of Alzheimer’s disease reverses these effects. 

Our current hypothesis is summarised in the model presented in Fig 1

 

 

 

2) A. Gene therapy approaches for Alzheimer’s disease.

            One of the major findings regarding the most common form of Alzheimer’s disease (Late onset Alzheimer’s disease) is that there is no single causative genetic factor is associated with the disease. We are currently collaborating with Prof. George Dickson and Dr. Linda Popplewell in developing tools that will allow us to target genes that are considered as “risk factors”.

We are developing CRISP/Cas9 gene editing approaches to modify various target genes,  as well as exon skipping approaches to correct possible mistakes in the splicing machinery of mature neurons (Fig 2 A).

2) B. Plant extracts as supplements: Can they protect in Alzheimer’s disease?

            Although it is mostly believed that senile plaques and Neurofibrilliary tangles is the established pathology of AD brains, accumulating evidence has shown that oxidative stress is an additional characteristic in the brains of these patients. Under normal conditions, damage by oxygen radicals is controlled by an efficient antioxidant system. However, during pathological conditions (such as in Alzheimer’s), this system is not efficient and reactive oxygen production exceeds cellular anti-oxidant defences causing oxidative damage.  One of our aims is to try and look for natural compounds that will penetrate the blood brain barrier and offer protection to neurons from the increased reactive oxygen (Fig 2 B)

 

 

Memory formation

The role of the adaptor protein Slap in homeostatic plasticity

Slap is a gene expressed in the cortex and the hippocampus. In collaboration with Prof V. Tarabykin (Charité - Universitätsmedizin Berlin, Germany) we have shown that upon EphA signalling, Slap is recruited along with NMDA receptors at synaptic sites in hippocampal neurons. Interestingly, its role is to induce activity-dependent degradation of NMDAR (Fig 2).

 

NMDA glutamate receptors have key roles in neuronal development and information storage in the mammalian brain. These receptors are glutamate-gated cation channels whose permeability to Ca2+ regulates significant aspects of synaptic plasticity. Furthermore, excess Ca2+ influx through NMDARs mediates cell death in certain neurodegenerative processes. Therefore, neurons must precisely control NMDAR levels.

 

 

 

 

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