STUDY MECHANISMS OF NEURODEGENERATION IN ALZHEIMER’S DISEASE

Abstract: 

It is considered that, independently of their triggering factor(s), the neurodegenerative pathways that lead to Alzheimer's Disease (AD) converge to the alteration of proteolysis or function of the Amyloid Precursor Protein (APP) because:

  • The Amyloid beta peptide (?‘?²), the main constituent of amyloid plaques that accumulate in AD brains, derives from APP processing.
  • Mutations in APP cause AD.
  • Mutations in presenilin 1(PS1), that forms the catalytic center of ?³-secretase that cleaves APP to produce ?‘?², cause also AD In addition, it is well documented that aberrant activation of the immune system contributes to the development of AD pathology.

Therefore, research has focused on the regulation of APP metabolism to limit production of ?‘?² and formation of amyloid plaques and on the role of the immune response in AD. We have discovered that Homer proteins, which regulate Ca2+ homeostasis, interact with APP and limit ?‘?² production. There is evidence that Ca2+ dyshomeostasis, as a secondary effect, contributes in AD while memantine, a drug that is used for AD treatment, regulates Ca2+ homeostasis. In parallel, we have obtained data indicating that autotoxin (ATX), a secreted phospholipase/diesterase that is implicated in inflammatory diseases, is involved in APP processing and that reduction of its levels reduces the size of amyloid plaques. Concomitantly, it has been shown that the levels of autotaxin mRNA are increased in AD brains. These results implicate ATX in AD.

Finally, genetic studies have shown that inheritance of the E4 allele of the APOE gene is the most significant risk factor for AD. ApoE regulates ?‘?² aggregation, formation of amyloid plaques, cholesterol homeostasis, atherosclerosis and the immune response, factors that play an important role in AD.

Our proposal aims at investigating the role of Homer, Ca2+ and ATX on APP interactions, metabolism and function as well as the role of ApoE on the AD immune response.

Project info

Acronym:
Neurad
Scientific Coordinator:
Efthimiopoulos Spyros
Research Team 2 Leader:
Skoulakis Efthymios
Research Team 3 Leader:
Georgopoulos Spiros

Stats

I.D.:
359
Mis:
380201
Duration (months):
44
Budget:
858 000.00
Diavgeia:
ΑΔΑ: Β41Ρ9-ΛΛΥ

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