IBYME   02675
INSTITUTO DE BIOLOGIA Y MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
artículos
Título:
Astroglial mGlu3 receptors promote alpha-secretase-mediated amyloid precursor protein cleavage
Autor/es:
D. DURAND; L. CARNIGLIA; J. BEAUQUIS; C. CARUSO; F. SARAVIA; M. LASAGA
Revista:
NEUROPHARMACOLOGY
Editorial:
PERGAMON-ELSEVIER SCIENCE LTD
Referencias:
Año: 2014 vol. 79 p. 180 - 189
ISSN:
0028-3908
Resumen:
Amyloid precursor protein (APP) shedding yields the Alzheimer's disease
(AD)-related peptide amyloid β (Aβ) through β- and γ-secretase cleavage.
Alternatively, α-secretase cleavage generates a soluble and
neuroprotective fragment (sAPPα) while precludes the production of Aβ.
Although metabotropic glutamate (mGlu) receptors were associated with
induction of sAPPα production in astrocytes, there was no further
evidence regarding the specific subtype receptor or the mechanisms
involved in this action. In the present study, we used the dual mGlu2/3
receptor agonist LY379268, which in pure astrocyte cultures selectively
activates mGlu3 receptor subtype since mGlu2 receptor subtype is not
expressed by these cells. We showed that LY379268 incremented sAPPα
release from cultured astrocytes by inducing α-secretases expression,
whereas it decreased β-secretase levels. LY379268-induced increase of
PPAR-γ levels could be involved in the effect of the agonist on sAPPα
release. Using the PDAPP-J20 murine model of AD we described a strong
reduction in mGlu2/3 receptor expression in the hippocampus of 5- and
14-month-old transgenic mice compared to control littermates. Moreover,
mGlu3 receptor expression is also decreased specifically in hippocampal
astrocytes of these transgenic animals as a function of age. Therefore,
diminished levels of hippocampal mGlu3 receptors might have implications
in the development of the disease in these transgenic mice considering
the anti-amyloidogenic action of mGlu3 receptors in astrocytes.