Research carried out by Angelique Camilleri as part of a research group at the University of Malta on how brain cells die in neurodegenerative diseases like Alzheimer’s dementia (AD) and Parkinson’s disease (PD) has yielded encouraging results that could be used to produce new medicines to treat these highly- debilitating conditions.

In AD, people gradually lose their memory and thinking skills, while in PD, an individual is afflicted by uncontrollable tremors and gross difficulty in movement. Unfortunately, medicines that can halt, or at least slow down, the inexorable progression of these diseases are still lacking. This places a huge burden on caregivers and family members, as well as a strain on the country’s finances. In the Maltese islands, around 8,000 individuals are presently suffering from AD or PD. More widely in the EU, these conditions afflict some eight million people.

At a neuropathological level, both AD and PD are characterised by damage to specific brain cells caused by the build-up and deposition of toxic clumps of abnormally folded proteins. In AD, these clumps consist of aggregates of amyloid-beta (plaques) and tau proteins (tangles); while in PD, the alpha-synuclein protein is the main component of the toxic deposits.

In her research, Dr Camilleri focused on using a variety of biochemical and biophysical techniques to uncover disease mechanisms at the single-molecule level which can be targeted by new medicines. Specifically, she sought to determine how the toxic protein clumps that deposit in the brains of individuals with AD or PD can affect the mitochondria of brain cells.

This opens up the possibility of new therapeutic benefits for plant-derived compounds in AD or PD

Mitochondria are the ‘powerhouses’ of brain cells and are crucial for providing them with energy: when mitochondria are compromised, brain cells inevitably die. Thus, experiments were performed in which healthy brain mitochondria were exposed to harmful clumps of tau and alpha-synuclein proteins. It was observed that these toxic entities induced leakage of critical biochemical components from the mitochondrial machinery, causing irreparable harm to the mitochondria.

Dr Camilleri also studied whether drug-like molecules could be found that might protect the mitochondria from being damaged by the toxic protein clumps. Interestingly, when mitochondria were incubated with compounds derived from natural plants – polyphenols like morin, baicalein, and black tea extract – the mitochondria appeared better able to withstand the deleterious effects of the toxic protein aggregates. This opens up the possibility of new therapeutic benefits for plant-derived compounds in AD or PD.

Dr Camilleri carried out the research for her thesis for a Doctor in Philosophy degree she was awarded by the University of Malta. Her research was conducted under the supervision of Neville Vassallo from the University’s Department of Physiology and Biochemistry.

Prof. Vassallo’s research group at the University’s Centre for Molecular Medicine and Biobanking is involved in a large collaborative effort on discovering new disease-modifying treatments for AD and PD, with scientists at the Ludwig-Maxi­-­milians-University of Munich, the German Centre for Neurodegenerative Diseases in Bonn, the Max Planck Institute for Biophysical Chemistry in Göttingen, and the University of California San Diego, among others.

A recent study was published by this group in the prestigious medical journal EMBO Molecular Medicine and was co-authored by Prof. Vassallo, Dr Camilleri and Dr Mario Caruana. The authors show that a potentially new medicine called ‘anle138b’ improved memory function in a mouse model of AD pathology.

Significantly, Prof. Vassallo’s team showed that the anle138b compound prevented mitochondrial damage and rescued brain cells from dying. Taken together, the data suggest that therapeutic effects can be expected to be achieved in AD patients with anle138b. There is also great promise of the compound in treating PD patients.

Angelique Camilleri was supported by a scholarship grant awarded by the Malta Government Scholarship Scheme. Neville Vassallo was supported by research grants from the Malta Council for Science and Technology through the National Research and Innovation Programme, the Faculty of Medicine and Surgery and the University of Malta.

http://embomolmed.embopress.org/content/early/2017/12/04/emmm.201707825.long