JPND LOss of neurotrophic factors in neurodegenerative DEmentias: Back to the crossroads of proteins (LODE)

Neurodegenerative diseases such as Alzheimer's and Parkinson's disease are very common in our society but how they develop and what we can do to treat them is not yet clear. Indeed no cure for these diseases is available. What is known is that some proteins in these diseases form abnormal aggregates that are associated with the death of the neuronal cells and disruption of the network in which neurons are integrated, leading to memory loss (like in Alzheimer's disease) or movement problems (like in Parkinson's disease). Exosomes are small vesicles that carry molecules between cells, and are very important in maintaining communication between neurons, especially when their networks are interrupted. We propose that ,the failure of exosomes to form and carry these molecules contributes to loss of neurons and disease. Neurons are supported by growth factors which are carried by exosomes, while exosome production in turn can depend on these growth factors but the mutual relationship between exosomes and growth factors is not well understood. The aim of this application is to clarify this relationship and exploit our findings to deliver growth factors that protect and support the neurons. To achieve these aims, we will examine the presence of these growth factors in exosomes and see if the deficiency can be overcome by delivering the growth factors using nanoparticles to human neurons from diseased individuals, transgenic mouse models of disease and test if the deficiency in patients with the disease. The results will help to shed light on new mechanisms contributing to neurodegeneration and may also unmask novel disease markers besides new targets for intervention.

The recognition that non-monogenic as well monogenic forms of dementia result substantially in the same disease, suggests that fundamental, simple mechanisms may underlie the apparent complexity of observed human neurodegenerative disorders. This project explores a key common pathological mechanism across AD, FTD, LBD. During conditions characterized by progressive loss of neurons, exosomes could become the key player of neuronal communication and the crossroads of proteins: accordingly, survival of neurons could be easily affected by factors modulating exosomes release and/or composition. Our working hypothesis is that loss of trophic factors is one of the main determinants affecting exosome release, thus influencing the fate of disease-related proteins across dementias. We envisage to address this issue by testing the link between i) neurotrophic factors and exosome generation (cellular and animal studies; neurobiological and neuropathological studies on patients); ii) exosome generation and neurodegeneration (cellular and animal studies; neurobiological, neuropathological and genetic studies on patients). To achieve these goals, we have organized a multidisciplinary team with a proven expertise in studying i) AD, FTD, LBD; ii) cellular and animal models; iii) human brain (neuropathology) and circulating disease markers; iv) proteins aggregation (abeta, tau, alpha-synuclein) v) exosome isolation/characterization; vi) genetic disease determinants; vii) nanoparticle delivery systems. LODE will achieve a great gain of knowledge regarding mechanisms of neurodegeneration but may also unmask novel disease markers and provide new targets for putative therapeutic intervention. Gender will be taken into account both in collecting and analysing data.

Forty million of people are affected by some form of dementia and only in the UK 127,000 people are affected by Parkinson's disease. No cure exists for these diseases and treatment for Parkinson's disease are only symptomatic. These diseases are characterised by different proteins aggregation and if a common pathway in their formation is identified, like the one we are suggesting in this application, it could be possible to design a mechanism based therapy that can be applied to all the protein aggregation-related neurodegenerative diseases affecting a large proportion of people in our ageing society and costing billions to governments. Further details about the impact are given in the attached application.