Borutaite MiP2010
| Borutaite V, Cizas P, Morkuniene R, Budvytyte R (2010) Effect of beta amyloid oligomers on neuronal viability and mitochondrial functions. |
Link: Abstracts Session 3
Borutaite V, Cizas P, Morkuniene R, Budvytyte R (2010)
Event: MiP2010
A growing body of evidence suggests that neurodegeneration in Alzheimerβs disease (AD) is related to extracellular and intracellular accumulation of amyloid beta peptide (AΞ²), mitochondrial dysfunction, increased neuronal loss, however the molecular pathways from AΞ² to the main pathological hallmarks of AD are still elusive. AΞ² molecules tend to aggregate and form complexes of varying size - from small soluble oligomers, bigger protofibrils and large insoluble fibrils. It is commonly assumed that formation of AΞ² fibrils is the crucial event in the pathogenesis of AD. However, there is accumulating evidence that soluble oligomers are the most cytotoxic forms of AΞ² though it is still unclear particles of which size and morphology exert most neurotoxicity. In our study we aimed to investigate a link between the size of soluble AΞ² oligomers and their toxicity to rat cerebellar granule cells (CGC), cortical neurons and other non-neuronal cells. Variation in conditions during in vitro oligomerization of AΞ²1-42 resulted in peptide assemblies with different particle size. Small oligomeric forms of AΞ²1-42 with a particle z-height of 1-2 nm (as measured by atomic force microscopy) were found to be the most toxic species, inducing rapid neuronal necrosis at submicromolar concentrations, whereas the bigger aggregates (above 4-5 nm) did not cause detectable neuronal death. AΞ²1-42 oligomers, monomers and fibrils were non-toxic to glial cells in CGC cultures or macrophage J774 cells. Small oligomers of AΞ² exhibited tendency to bind to the phospholipid vesicles which composition was similar to reported neuronal plasma membrane composition. In contrast, bigger, non-toxic oligomers did not bind to phospholipid vesicles.
We also found that mitochondrial respiratory functions were not affected by AΞ²1-42 irrespective of the aggregate state: monomers, oligomers or fibrils of AΞ² at concentrations up to 2 Β΅M did not inhibit state 3 and state 4 respiration of isolated brain mitochondria and did not cause permeabilization of mitochondrial outer membrane as measured by the exogenous cytochrome c test on mitochondrial respiration. This suggests that AΞ²1-42 at pathophysiologically relevant concentrations has no acute effect on mitochondria.
In conclusion, our data demonstrate that small oligomers of AΞ² at submicromolar concentrations induce rapid neuronal necrosis most likely due to the effect on neuronal plasma membranes, whereas bigger aggregates are not directly toxic to neurons.
β’ Keywords: Alzheimerβs disease (AD), Amyloid beta peptide (AΞ²), Cerebellar granule cells (CGC), Cortical neurons, Glial cells
β’ O2k-Network Lab: LT Kaunas Borutaite V
Labels:
Stress:Mitochondrial Disease; Degenerative Disease and Defect"Mitochondrial Disease; Degenerative Disease and Defect" is not in the list (Cell death, Cryopreservation, Ischemia-reperfusion, Permeability transition, Oxidative stress;RONS, Temperature, Hypoxia, Mitochondrial disease) of allowed values for the "Stress" property. Organism: Rat Tissue;cell: Nervous system Preparation: Isolated Mitochondria"Isolated Mitochondria" is not in the list (Intact organism, Intact organ, Permeabilized cells, Permeabilized tissue, Homogenate, Isolated mitochondria, SMP, Chloroplasts, Enzyme, Oxidase;biochemical oxidation, ...) of allowed values for the "Preparation" property.
Coupling state: LEAK
