RICERCA ITALIANA     

Pathogenetic role of Brain-derived neurotrophic factor (BDNF) in the aetioloogy of neurodegenerative disorders: from animal models to human study.

Università degli Studi di Brescia

Abstract

Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are a unique family of polypeptide growth factors that influence differentiation and survival of neurons in the developing nervous system, thus being likely involved in neurodegenerative disorders. Neurotrophins might represent a breakthrough in the treatment of Alzheimer Disease (AD) and other neurodegenerative disorders, as recent clinical trials shown benefit from their exogenous application.
Among others, BDNF has been widely studied both in human genetic studies and in in vitro studies.
A functional polymorphism within BDNF gene consisting of a missense change (G196A) has been described. BDNF Val/Met polymorphism has been previously suggested as a genetic risk factor for Alzheimer Disease (AD), even if with conflicting results, and no data on other neurodegenerative disorders are available yet. Its role in neurodegeneration has also been supported by the evidence that in the AD brain, decreased BDNF protein levels were reported in hippocampus, entorhinal cortex, and temporal neocortex while no changes were observed in areas less affected by the disease, such as the frontal, parietal, and cerebellar cortices.
These observations, taken together, underline the need of a deeper knowledge of BDNF functions and its modifications in neurodegenerative process. The study of genetic, epigenetic and posttrasductional BDNF mechanisms are of interest for their crucial role in neuronal loss and >>>

Principal Investigator

Alessandro Padovani Università degli Studi di BRESCIA

Research Objectives

The aim of this project will be to evaluate the role of neurotrophin, such as BDNF, in the pathogenesis of neurodegenerative disorders.
The work will be divided into two different steps, the first will be aimed at evaluating the
role of BDNF in vivo, in patients affected by different neurodegenerative disorders, such as AD, FTD or PD.
The second step will be dedicated at in vitro and in animal studies for establishing the role of BDNF in models of neurodegeneration.

In particular, the objectives of this study will be the followings:


- In human study
1) To investigate in a wide sample of subjects with neurodegenerative disorders and age-matched healthy controls the role of genetic predisposing variations within BDNF gene in determining the risk of AD and other neurodegenerative diseases, i.e. FTD and PD.
Three-hundred twenty subjects (110 AD, 110 age-matched controls and 100 patients with neurodegenerative disorders other than AD) will be enrolled. To this aim, four different BDNF polymorphisms will be evaluated such as BDNF Val66Met, BDNF C270T, BDNF G11757C, and BDNF – T633A. The single SNPs analysis and the haplotype analysis will be performed across patient groups and controls.

2) To investigate the role of epigenetic variations, i.e. BDNF gene promoter methylation, in determining the risk of AD and other neurodegenerative diseases, i.e. FTD and PD.
The correlations between BDNF >>>

First Results

We strongly believe that the proposed research program may represent an important contribution to the definition of the role of neurotrophines, such as BDNF, in AD and other neurodegenerative disorders.
This project will be divided into two steps.
The first step will be mainly devoted to the enrolment of normal controls, patients with AD and patients with other neurodegenerative diseases, such as FTD, PD or PD with dementia, and to the preparation and standardisation of protocols shared by all the Units for neuropsychological assessment and blood sampling. The research protocol, including the inclusion/exclusion criteria, will allow to select a relatively large sample of patients where to test the effect of BDNF, compared with previous studies reported in literature. The single SNP analysis and the haplotype analysis will be conducted in AD patients, in other neurodegenerative disorders and in aged-matched healthy control subjects. This will represent the first study on the issue (1nd result). Indeed, the methodological approach based on the use of haplotypes can allow to get more information on the influence of a gene on the pathogenesis of a disease, with respect to a classical model based on the analysis of a single polymorphism. To circumvent the difficulty of molecular haplotyping, several methods based on statistical inference will be proposed to estimate haplotype frequencies from genotypic data and their correlations with clinical and biological >>>

Timescale

24 months

National and international background

Establishing the targets of neurodegeneration and neuroprotection is crucial for more effective treatment strategies.
Previous studies have suggested that neurodegenerative diseases are the results of a complex interaction of genetic predisposing factors, defective neuroprotective strategies and damage due to inflammation, involving specific cerebral pathways. In this view, the role of neurotrophic factors, which are demonstrated to be involved in modulation of learning mechanisms, are critical.
Among these, the brain-derived neurotrophic factor (BDNF) is a polypeptide fundamental in survival, differentiation and growth of the peripheral and central neurons both during and after development. The BDNF mature protein derives from uncleaved precursor BDNF protein, pro-BDNF. It binds to a specific receptor and selectively interacts with protein-tyrosine kinase receptors type B (trkB), that are present both in pre- and post-synaptic membranes. The BDNF promotes cell survival and it is involved in neuronal homeostasis and brain plasticity-related processes such as memory and learning. Animal studies have observed that in the brain, BDNF mRNA and protein expression becomes detectable during embryonic development, reaching the highest levels by days10-14 postnatally and decreasing thereafter. In the adult animal brain, BDNF is expressed throughout the brain, with the highest levels in hippocampus; a similar distribution with high levels of BDNF in cortical areas, such >>>