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INIZIO_TESTO_DA_INDICIZZARE

RESEARCH PROGRAM

italiano - inglese
Research Units
Similar research programs:
Scientific and education field classification
International Patent Classification
Geographical classification
Keywords
ALZHEIMER'S DISEASE; BETA AMYLOID PEPTIDES; CALCIUM; OXIDATIVE STRESS; APOPTOSIS PATHWAYS; PROTEASOME; TRASCRIPTION FACTORS; FIBRILLOGENESIS INHIBITORS; TRANSGENIC MICE

Molecular bases of cytotoxicity by distinct beta-amyloid specific misfolding/aggregation states: a comprehensive investigation in vitro, in cultured cells and in animal model

Università degli Studi di Firenze
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by three main structural changes in the brain: diffuse loss of neurons in the hippocampus and neocortex, accumulation of intracellular protein deposits termed neurofibrillary tangles and extracellular formation of senile plaques. The amyloid core of senile plaques consists of deposits of β-amyloid (Aβ) protein. The hypofunction of cholinergic neurons in the cortex and hippocampus contributes significantly to the cognitive symptoms associated with AD. Unknown is still the mechanism behind neurodegeneration and the "amyloid cascade" hypothesis has defined the fibrillation of Aβ into amyloid plaques as the primary culprit in the neurotoxicity. According to this hypothesis, Aβ undergoes, over a period of time, conformational changes concomitant with self assembly into oligomers, profibrils, fibrils until they are deposited in senile plaques. Despite the large number of researches on this issue, whether or not this is an unbreakable and irreversible process and the biological role of the different Aβ aggregation states remain to be established. A central role of oxidative stress in AD pathogenesis has been suggested and Aβ combination with the brain's intrinsic supply of Cu2+, Zn2+ and Fe2+ mediates the peptide's aggregation and toxicity, through hydrogen peroxide production. In AD, the oxidation injury is mediated by the generation of hydrogen peroxide and the scavenging defences >>>

Principal Investigator
Gianfranco LIGURI Università degli Studi di FIRENZE
Research Objectives
This proposal aims to clarify the molecular bases of neuronal death upon exposure to misfolded and aggregated Abeta species by experiments carried out in vitro, in cultured cells and in an animal model. Structural, molecular and biological basis of Abeta aggregate formation and toxicity to cultured cells and the differential susceptibility to toxicity will be studied on cultured human neuroblastoma cells and Alzheimier's fibroblasts. In particular we will investigate specific intracellular pathways occurring during a neurodegenerative process where free radical production has been demonstrated to be the major contributor. Furthermore we will test antioxidant compounds (such as glutathione esters and thioesters) and compounds endowed with the property to interfere with Abeta fibrillogenesis (i.e. clioquinol) on Abeta-induced neurotoxicity. The main goal of this project is to answer the following questions: 1) how the different Abeta; aggregation states affect neuronal cell function; 2) are free radicals and calcium homeostasis involved in the conformation-specific Abeta toxicity; 3) which signal transduction and apoptosis pathways are affected, and 4) is it possible to identify molecules able to reinforce the cellular defences against Abeta toxicity or to shift the equilibrium between the different Abeta aggregation states so as to reduce deleterious vs not-deleterious Abeta species?

In particular, the following tasks will be pursued:

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Timescale
24 months
National and international background
People suffering of Alzheimer's disease (AD) develop a progressive dementia in adulthood, accompanied by three main structural changes in the brain: diffuse loss of neurons in the hippocampus and neocortex, accumulation of intracellular protein deposits termed neurofibrillary tangles and extracellular formation of senile plaques. The amyloid core of senile plaques consists of deposits of β-amyloid (Aβ) protein (1,2). The hypofunction of cholinergic neurons in the cortex and hippocampus, areas of the brain associated with memory and higher intellectual functioning, contributes significantly to the cognitive symptoms associated with AD (3). Aβ deposits in AD patients are almost exclusively composed of the highly amyloidogenic 1-42 form (Aβ 1-42), which is normally produced by cells in much lower quantities than the 40 residues form (Aβ 1-40). Aβ 1-42 is most prone to self-aggregation in vitro respect to Aβ 1-40 and its citotoxicity is considered the main responsible of neuronal impairment in AD (99). It has been reported, in familial Alzheimer's disease (FAD) patients, an early increase in the production of the Aβ 1-42 arising from the intracellular processing of amyloid precursor protein (APP) (4). Interestingly, all the observed mutations associated with FAD cases independently lead to an increased production of Aβ (5). Under physiological conditions, Aβ peptides are generated by cleavage of APP by alfa-, beta- and >>>