Artículo
A metabotropic glutamate receptor 3 (mGlu3R) isoform playing neurodegenerative roles in astrocytes is prematurely up-regulated in an Alzheimerʼs model
Turati, Juan
; Rudi, Julieta; Beauquis, Juan
; Carniglia, Lila
; López Couselo, Federico
; Saba, Julieta
; Caruso, Carla Mariana
; Saravia, Flavia Eugenia
; Lasaga, Mercedes Isabel
; Durand, Daniela Elizabeth
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Fecha de publicación:
05/2022
Editorial:
Wiley Blackwell Publishing, Inc
Revista:
Journal of Neurochemistry
ISSN:
0022-3042
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
Subtype 3 metabotropic glutamate receptor (mGlu3R) displays a broad range of neuroprotective effects. We previously demonstrated that mGlu3R activation in astrocytes protects hippocampal neurons from Aβ neurotoxicity through stimulation of both neurotrophin release and Aβ uptake. Alternative-spliced variants of mGlu3R were found in human brains. The most prevalent variant, mGlu3Δ4, lacks exon 4 encoding the transmembrane domain and can inhibit ligand binding to mGlu3R. To date, neither its role in neurodegenerative disorders nor its endogenous expression in CNS cells has been addressed. The present paper describes for the first time an association between altered hippocampal expression of mGlu3Δ4 and Alzheimer´s disease (AD) in the preclinical murine model PDAPP-J20, as well as a deleterious effect of mGlu3Δ4 in astrocytes. As assessed by western blot, hippocampal mGlu3R levels progressively decreased with age in PDAPP-J20 mice. On the contrary, mGlu3Δ4 levels were drastically increased with aging in nontransgenic mice, but prematurely overexpressed in 5-month-old PDAPP-J20-derived hippocampi, prior to massive senile plaque deposition. Also, we found that mGlu3Δ4 co-precipitated with mGlu3R mainly in 5-month-old PDAPP-J20 mice. We further showed by western blot that primary cultured astrocytes and neurons expressed mGlu3Δ4, whose levels were reduced by Aβ, thereby discouraging a causal effect of Aβ on mGlu3Δ4 induction. However, heterologous expression of mGlu3Δ4 in astrocytes induced cell death, inhibited mGlu3R expression, and prevented mGlu3R-dependent Aβ glial uptake. Indeed, mGlu3Δ4 promoted neurodegeneration in neuron?glia co-cultures. These results provide evidence of an inhibitory role of mGlu3Δ4 in mGlu3R- mediated glial neuroprotective pathways, which may lie behind AD onset.
Palabras clave:
AGING
,
ALZHEIMER'S DISEASE
,
ASTROCYTES
,
MGLU3R
,
MGLU3Δ4
,
SPLICING
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Identificadores
Colecciones
Articulos(IBYME)
Articulos de INST.DE BIOLOGIA Y MEDICINA EXPERIMENTAL (I)
Articulos de INST.DE BIOLOGIA Y MEDICINA EXPERIMENTAL (I)
Articulos(INBIOMED)
Articulos de INSTITUTO DE INVESTIGACIONES BIOMEDICAS
Articulos de INSTITUTO DE INVESTIGACIONES BIOMEDICAS
Citación
Turati, Juan; Rudi, Julieta; Beauquis, Juan; Carniglia, Lila; López Couselo, Federico; et al.; A metabotropic glutamate receptor 3 (mGlu3R) isoform playing neurodegenerative roles in astrocytes is prematurely up-regulated in an Alzheimerʼs model; Wiley Blackwell Publishing, Inc; Journal of Neurochemistry; 161; 4; 5-2022; 366-382
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