beta-Amyloid peptide induces ultrastructural changes in synaptosomes and potentiates mitochondrial dysfunction in the presence of ryanodine.
In Alzheimer's disease (AD), loss of synapses exceeds neuronal loss and some evidence suggests a role of beta-amyloid protein (Abeta) in synaptic degeneration through a mechanism which may involve intraneuronal Ca2+ dyshomeostasis. Emerging evidence points to the participation of the internal Ca2+ stores in the pathophysiology of neurodegeneration in AD. To test the involvement of intrasynaptic Ca2+ mobilization in A toxicity, we explored the role of ryanodine receptor activation in rat cortical synaptosomes taken as a model system for the central presynapses. Evaluation of synaptosomal mitochondrial redox capacity was assessed by the MTT reduction technique, and ultrastructural changes of synaptosomes after exposure to Abeta and ryanodine were evaluated by electron microscopy. Our results show that Abeta potentiates mitochondrial dysfunction in the presence of ryanodine and induces morphological changes consisting of mitochondrial swelling and intense small synaptic vesicles depletion. These changes were accompanied by a reduction in the content of synaptophysin and actin proteins. The reduction of actin immunoreactivity was reversed in the presence of a wide range caspase inhibitors, suggesting the activation of synaptic apoptotic mechanisms.
Mungarro-Menchaca
Xavier
X
Departamento de Biología Celular y Fisiologia, Instituto de Investigaciones Biomédicas Universidad Nacional Autónoma de México, D.F.
Ferrera
Patricia
P
Morán
Julio
J
Arias
Clorinda
C
D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000187:drug effects; D008297:Male; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012433:Ryanodine / Q000494:pharmacology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism; D013574:Synaptosomes / Q000502:physiology* / Q000648:ultrastructure
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D019837:Ryanodine Receptor Calcium Release Channel; C074636:amyloid beta-protein (25-35); D012433:Ryanodine; D002118:Calcium