GSK3β overexpression induces neuronal death and a depletion of the neurogenic niches in the dentate gyrus.
Overexpression of GSK3β in transgenic mice induces learning deficits and some features associated with Alzheimer's disease (AD), including dentate gyrus (DG) atrophy. Here, we assessed whether these mice also recapitulate DG atrophy as well as impaired neurogenesis reported in AD. Ultrastructural analysis revealed that there were fewer and more disorganized neurogenic niches in these animals, coupled with an increase in the proportion of immature neurons. Indeed, the maturation of granule cells is delayed as witnessed by the alterations to the length and patterning of their dendritic trees and to the mossy fiber terminals. Together with an increase in neuronal death, these phenomena lead to a marked decrease in the number and disorganization of granule cells of the DG. Our results suggest that GSK3β overexpression perturbs proliferation and maturation, resulting in the loss of immature neurons. In turn, the activation of microglia is stimulated in conjunction with a decrease in the birth of new functional neurons, leading to the deterioration of this structure. These data support the idea that by inducing degeneration of the DG, GSK3β could be involved in the pathogenesis of AD.
Sirerol-Piquer
Masalomé
M
Departamento de Neurobiología Comparada, Instituto Cavanilles, Universidad de Valencia, Spain.
Gomez-Ramos
Pilar
P
Hernández
Félix
F
Perez
Mar
M
Morán
María A
MA
Fuster-Matanzo
Almudena
A
Lucas
José J
JJ
Avila
Jesús
J
García-Verdugo
Jose Manuel
JM
D000544:Alzheimer Disease / Q000503:physiopathology*; D000818:Animals; D016923:Cell Death; D002454:Cell Differentiation; D049109:Cell Proliferation; D018891:Dentate Gyrus / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia; D055495:Neurogenesis
C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3