Ο ρόλος της απολιποπρωτεΐνης Ε στην παθογένεση της νόσου του Alzheimer

Apolipoprotein E (apoE) is a major protein of the lipoprotein transport system that plays critical roles in atherosclerosis, dyslipidemia and Alzheimer's disease (AD). ApoE contains 299 residues and has three common isoforms (apoE2, apoE3, apoE4) in the general population. The apoE4 isoform is a major genetic risk factor for AD. AD is the most common cause of dementia in the elderly. It is characterized clinically by progressive decline in memory, executive function, language, and other areas of cognition. Pathologically, there is formation of amyloid plaques and neurofibrillary tangles in the brain, as well as neuronal loss, synaptic loss, brain atrophy, and inflammation. Accumulation of the amyloid- peptide (A ) outside or inside neurons is hypothesized to initiate a pathogenic cascade that eventually leads to AD. The sequential proteolytic processing of amyloid precursor protein (APP) by -secretase and -secretase produces several A species, including the most abundant 40 amino acid species (A 40) and a number of minor species, including the more amyloidogenic A 42. There have been numerous studies attempting to elucidate how apoE4 influences AD onset and progression. Prevailing evidence suggests that the differential effects of apoE isoforms on A aggregation and clearance play the major role in AD pathogenesis. ApoE4 is more susceptible to proteolysis than other apoE isoforms and apoE4 fragments have been found in brains of AD patients. These apoE4 fragments have been hypothesized to be involved in the pathogenesis of AD, although the mechanism is not clear. In our studies we examined the effect of apoE4 on APP processing and Aβ40 and Aβ42 levels in human neuroblastoma SK-N-SH cells. We discovered that a specific apoE4 fragment, apoE4[ (166-299)], can promote the cellular uptake of extracellular A 40 and A 42 either generated after APP transfection or added exogenously. A longer length fragment, apoE4[ (186-299)], or full-length apoE4 failed to elicit this effect. ApoE4[ (166-299)] led to 20% reduction of cellular sphingomyelin levels, a reduction that may be related to Aβ cellular uptake. Following uptake, approximately 50% of Α 42 remained within cells after 24h and led to increased formation of reactive oxygen species (ROS). Overall, our findings suggest a possible mechanism that links two early events in the pathogenesis of AD, apoE4 proteolysis and intraneuronal presence of Aβ.

Ομιλήτρια: Α. Χρόνη
Ερευνήτρια Β , Ινστιτούτο Βιολογίας, ΕΚΕΦΕ "Δημόκριτος"
Ώρα: Δευτέρα, 8 Φεβρουαρίου 2010, 13:00