|Borutaite V, Cizas P, Morkuniene R, Budvytyte R (2010) Effect of beta amyloid oligomers on neuronal viability and mitochondrial functions.|
Link: Abstracts Session 3
A growing body of evidence suggests that neurodegeneration in Alzheimer‘s disease (AD) is related to extracellular and intracellular accumulation of amyloid beta peptide (Aβ), mitochondrial dysfunction, increased neuronal loss, however the molecular pathways from Aβ to the main pathological hallmarks of AD are still elusive. Aβ 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 Aβ fibrils is the crucial event in the pathogenesis of AD. However, there is accumulating evidence that soluble oligomers are the most cytotoxic forms of Aβ 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 Aβ 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 Aβ1-42 resulted in peptide assemblies with different particle size. Small oligomeric forms of Aβ1-42 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. Aβ1-42 oligomers, monomers and fibrils were non-toxic to glial cells in CGC cultures or macrophage J774 cells. Small oligomers of Aβ 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 Aβ1-42 irrespective of the aggregate state: monomers, oligomers or fibrils of Aβ at concentrations up to 2 µM 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 Aβ1-42 at pathophysiologically relevant concentrations has no acute effect on mitochondria.
In conclusion, our data demonstrate that small oligomers of Aβ 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.
• Keywords: Alzheimer‘s disease (AD), Amyloid beta peptide (Aβ), Cerebellar granule cells (CGC), Cortical neurons, Glial cells
• O2k-Network Lab: LT Kaunas Borutaite V
Stress:Mitochondrial disease Organism: Rat Tissue;cell: Nervous system Preparation: Isolated mitochondria
Coupling state: LEAK