Glutamatergic alterations and mitochondrial impairment in a murine model of Alzheimer disease.
Deficits in glutamate neurotransmission and mitochondrial functions were detected in the frontal cortex (FC) and hippopcampus (HIPP) of aged 3×Tg-Alzheimer's disease (AD) mice, compared with their wild type littermates (non-Tg). In particular, basal levels of glutamate and vesicular glutamate transporter 1 (VGLUT1) expression were reduced in both areas. Cortical glutamate release responded to K(+) stimulation, whereas no peak release was observed in the HIPP of mutant mice. Synaptosomal-associated protein 25 (SNAP-25), glutamate/aspartate transporter (GLAST), glutamate transporter 1 (GLT1) and excitatory amino acid carrier 1 (EAAC1) were reduced in HIPP homogenates, where the adenosine triphosphate (ATP) content was lower. In contrast, glutamate transporter 1 and glial fibrillary acidic protein (GFAP) were found to be higher in the frontal cortex. The respiration rates of complex-I, II, IV, and the membrane potential were reduced in cortical mitochondria, where unaltered proton leak, F(0)F(1)-ATPase activity and ATP content, with increased hydrogen peroxide production (H(2)O(2)), were also observed. In contrast, complex-I respiration rate was significantly increased in hippocampal mitochondria, together with increased proton leak and H(2)O(2) production. Moreover, loss of complex-IV and F(0)F(1)-ATPase activities were observed. These data suggest that impairments of mitochondrial bioenergetics might sustain the failure in the energy-requiring glutamatergic transmission.
Department of Biomedical Sciences, University of Foggia, Foggia, Italy. tommaso.cassano@gmail.com
Tommaso
T
Cassano
Gaetano
G
Serviddio
Silvana
S
Gaetani
Adele
A
Romano
Pasqua
P
Dipasquale
Silvia
S
Cianci
Francesco
F
Bellanti
Leonardo
L
Laconca
Antonino Davide
AD
Romano
Iolanda
I
Padalino
Frank M
FM
LaFerla
Ferdinando
F
Nicoletti
Vincenzo
V
Cuomo
Gianluigi
G
Vendemiale
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D004195:Disease Models, Animal; D027341:Excitatory Amino Acid Transporter 1 / Q000235:genetics / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism; D018698:Glutamic Acid / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology*; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics / Q000378:metabolism; D050598:Vesicular Glutamate Transport Protein 1 / Q000235:genetics / Q000378:metabolism
D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; C493465:Slc17a7 protein, mouse; C493396:Slc1a2 protein, mouse; C493393:Slc1a3 protein, mouse; C494209:Snap25 protein, mouse; D050825:Synaptosomal-Associated Protein 25; D050598:Vesicular Glutamate Transport Protein 1; D018698:Glutamic Acid