Down-regulation of glutamatergic terminals (VGLUT1) driven by Aβ in Alzheimer's disease.
Alzheimer's disease (AD) is characterized phenotypically by memory impairment, histologically by accumulation of pTau and β-amyloid peptide and morphologically by a loss of nerve terminals in cortical and hippocampal regions. As glutamate is the principle excitatory neurotransmitter of the central nervous system (CNS), the glutamatergic system may play an important role in AD. To date, not many studies have addressed the deleterious effects of Aβ on glutamatergic terminals; therefore the aim of this study was to investigate how Aβ affects glutamatergic terminals and to assess the extent to which alterations in the glutamatergic neurotransmission could impact susceptibility to the illness. The present study shows that Aβ caused a loss of glutamatergic terminals, measured by VGLUT1 protein levels, in Tg2576 primary cell cultures, Tg2576 mice and AD patient brains, and also when Aβ was added exogenously to hippocampal cell cultures. Interestingly, no correlation was found between cognition and decreased VGLUT1 levels. Moreover, when Aβ1-42 was intracerebroventricularlly administered into VGLUT1+/- mice, altered synaptic plasticity and increased neuroinflammation was observed in the hippocampus of those animals. In conclusion, the present study not only revealed susceptibility of glutamatergic nerve terminals to Aβ induced toxicity but also underlined the importance of VGLUT1 in the progression of AD, as the decrease of this protein levels could increase the susceptibility to subsequent deleterious inputs by exacerbating Aβ induced neuroinflammation and synaptic plasticity disruption. © 2016 Wiley Periodicals, Inc.
Department of Pharmacology and Toxicology, University of Navarra, Pamplona 31008, Spain.
Manuel
M
Rodriguez-Perdigon
Department of Pharmacology and Toxicology, University of Navarra, Pamplona 31008, Spain.|IdiSNA Navarra Institute for Health Research, Pamplona, Spain.
Rosa María
RM
Tordera
Center for Applied Medical Research (CIMA), Neuroscience, University of Navarra, Pamplona, Spain.
Francisco Javier
FJ
Gil-Bea
Department of Pharmacology and Toxicology, University of Navarra, Pamplona 31008, Spain.
Gorka
G
Gerenu
Department of Pharmacology and Toxicology, University of Navarra, Pamplona 31008, Spain.|IdiSNA Navarra Institute for Health Research, Pamplona, Spain.
Maria Javier
MJ
Ramirez
Department of Pharmacology and Toxicology, University of Navarra, Pamplona 31008, Spain. msolaszu@unav.es.|IdiSNA Navarra Institute for Health Research, Pamplona, Spain. msolaszu@unav.es.
Maite
M
Solas
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D050598:Vesicular Glutamate Transport Protein 1 / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016194:Receptors, N-Methyl-D-Aspartate; C493464:SLC17A7 protein, human; C493465:Slc17a7 protein, mouse; D050598:Vesicular Glutamate Transport Protein 1; D018698:Glutamic Acid
GFAP; beta-amyloid; cognition; glutamate; neuroinflammation