Mitochondria in Excitatory and Inhibitory Synapses have Similar Susceptibility to Amyloid-β Peptides Modeling Alzheimer's Disease.

Abstract

Mitochondrial dysfunction is proposed to trigger memory deficits and synaptic damage at the onset of Alzheimer's disease (AD). However, it is unknown how mitochondria dysfunction might trigger synaptotoxicity and if a differential susceptibility of mitochondria located in synapses underlies the greater glutamatergic than GABAergic synaptotoxicity in early AD. Hippocampal synaptosomes (purified synapses) of a rat model of early AD, typified by selective memory deficits two weeks after intracerebroventricular injection of amyloid-β peptides (Aβ1-42, 2 nmol), simultaneously displayed three mitochondria-associated deleterious alterations: 1) hampered metabolism (decreased MTT reduction); 2) increased oxygen radical production (increased hydrogen peroxide production); 3) increased caspase-3 activity. The direct exposure of hippocampal synaptosomes to Aβ1-42 (500 nM) similarly decreased mitochondrial membrane potential (TMRM+ fluorescence) and increased mitochondria-derived oxygen radicals (MitoTraker®red-CM-H2Xros fluorescence) in individual glutamatergic (vesicular glutamate transporter-immunopositive) and GABAergic (vesicular GABA transporter-immunopositive) synaptosomes. However, significantly more glutamatergic than GABAergic synaptosomes were endowed with mitochondria (Tom20-immunopositive). These results indicate that dysfunctional mitochondria located in synapses can trigger synaptotoxicity through multifaceted mechanisms and that it is not the susceptibility of mitochondria to Aβ but more likely a different impact of dysfunctional mitochondria that underlies the greater sensitivity to synaptotoxicity of glutamatergic than GABA synapses in early AD.