The most common neurodegenerative disorder of the central nervous system in the developed countries is Alzheimer's disease (AD), whose incidence is increasing exponentially with increasing age. It represents a serious social problem, as the cost of patient care are very high and there is still no effective treatment. The development of new effective therapies is therefore a strong current priority.

Nowadays it is considered that the primary cause of the disease is increasing production of polypeptides of beta-amyloid (especially the variants with a length of 42 amino acids), whose soluble oligomers are neurotoxic. They then gradual polymerize and form amyloid plaques that are characteristic histopathologic feature of the disease. The cause of increased production of beta‑amyloid is known for familial (contingent known defect in the genes for amyloid precursor protein, presenilin 1 and presenilin 2) forms of the disease, but these forms represent only a tiny fraction (1-2% ) of all diseases. In all other cases, the cause of the increased production of amyloid is unknown. Unclear are also the mechanisms that are involved in the initial synaptotoxic effects of beta‑amyloid. The most significant risk factors for disease confirmed in humans are aging and the presence of allelic variants of apolipoprotein E (ApoE) ApoE4. Its presence lowers the age at which there is a manifestation of the disease. Concerning aging it is not known what mechanisms play role in the disease. It is believed that repeated exposure to various injuries and poisoning during life contributes to the disease. One of the immutable characteristics of the disease is the damage to the cholinergic neurons that are very sensitive to different intoxications and hypoxia. Cholinergic transmission disorders result in the increased production of beta‑amyloid. The role of cholinergic transmission in the pathogenesis of the disease is also supported by the fact that most of drugs approved for the treatment of Alzheimer's disease enhances cholinergic transmission.

Apolipoprotein E4 is the most prevalent genetic risk factor of Alzheimer’s disease. The overall objective of this project is to investigate the cellular and molecular mechanisms underlying the neuronal and synaptic effects of apoE4 and their neuronal specificity: This will first be pursued by an hypothesis driven approach, which stems from our preliminary results, and will focus on the hypothesis that Aβ, tau protein, and mitochondria mediate the neuron specific effects of apoE4. The possible role of additional mechanisms will be investigated by nonbiased proteomic analysis of the effects of apoE4 on the levels and repertoire of synaptic proteins in distinct cholinergic and glutamatergic nerve terminals. This study is expected to further our understanding of the mechanisms underlying neuronal specificity of neurodegeneration in AD. Furthermore, the insight to be gained is expected to have important medical applications and to assist in the design and development of novel therapeutic strategies.