Apolipoprotein D Overexpression Protects Against Kainate-Induced Neurotoxicity in Mice.
Excitotoxicity due to the excessive activation of glutamatergic receptors leads to neuronal dysfunction and death. Excitotoxicity has been implicated in the pathogenesis of a myriad of neurodegenerative diseases with distinct etiologies such as Alzheimer's and Parkinson's. Numerous studies link apolipoprotein D (apoD), a secreted glycoprotein highly expressed in the central nervous system (CNS), to maintain and protect neurons in various mouse models of acute stress and neurodegeneration. Here, we used a mouse model overexpressing human apoD in neurons (H-apoD Tg) to test the neuroprotective effects of apoD in the kainic acid (KA)-lesioned hippocampus. Our results show that apoD overexpression in H-apoD Tg mice induces an increased resistance to KA-induced seizures, significantly attenuates inflammatory responses and confers protection against KA-induced cell apoptosis in the hippocampus. The apoD-mediated protection against KA-induced toxicity is imputable in part to increased plasma membrane Ca2+ ATPase type 2 expression (1.7-fold), decreased N-methyl-D-aspartate receptor (NMDAR) subunit NR2B levels (30 %) and lipid metabolism alterations. Indeed, we demonstrate that apoD can attenuate intracellular cholesterol content in primary hippocampal neurons and in brain of H-apoD Tg mice. In addition, apoD can be internalised by neurons and this internalisation is accentuated in ageing and injury conditions. Our results provide additional mechanistic information on the apoD-mediated neuroprotection in neurodegenerative conditions.
Laboratoire de Biologie Moléculaire, Département des Sciences Biologiques, Centre BioMed, Université du Québec à Montréal, Case Postale 8888, Succursale Centre-ville, Montréal, QC, H3C-3P8, Canada.
Ouafa
O
Najyb
Laboratoire de Biologie Moléculaire, Département des Sciences Biologiques, Centre BioMed, Université du Québec à Montréal, Case Postale 8888, Succursale Centre-ville, Montréal, QC, H3C-3P8, Canada.|Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
Sonia
S
Do Carmo
Laboratoire de Biologie Moléculaire, Département des Sciences Biologiques, Centre BioMed, Université du Québec à Montréal, Case Postale 8888, Succursale Centre-ville, Montréal, QC, H3C-3P8, Canada.
Azadeh
A
Alikashani
Laboratoire de Biologie Moléculaire, Département des Sciences Biologiques, Centre BioMed, Université du Québec à Montréal, Case Postale 8888, Succursale Centre-ville, Montréal, QC, H3C-3P8, Canada. rassart.eric@uqam.ca.
Eric
E
Rassart
D000818:Animals; D053399:Apolipoproteins D / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D004705:Endocytosis; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000473:pathology; D007608:Kainic Acid / Q000633:toxicity*; D008822:Mice, Transgenic; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D000066829:Neuroprotection / Q000187:drug effects; D009498:Neurotoxins / Q000633:toxicity*; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012640:Seizures / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects
D053399:Apolipoproteins D; D009498:Neurotoxins; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D002784:Cholesterol; D053499:Plasma Membrane Calcium-Transporting ATPases; D007608:Kainic Acid
Apolipoprotein D (apoD); Apoptosis; Calcium; Cholesterol metabolism; Excitotoxicity; Inflammation; Kainic acid; Neurodegenerative diseases; Seizure