Apolipoprotein D Overexpression Protects Against Kainate-Induced Neurotoxicity in Mice

Abstract

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.

Mesenchymal Stem Cell-Secreted Exosome Promotes Chemoresistance in Breast Cancer via Enhancing miR-21-5p-Mediated S100A6 Expression

“…Among the 75 candidate genes shown in Figures 3 A and 3B, S100A6 , 15 FosB , 16 ARHGDIB , 17 SOD3 , 18 and ApoD 19 have been previously implicated in promoting cell survival. Further RT-PCR validation showed that only the top-ranked S100A6 showed corresponding induction in BCs in response to exosome treatment ( Figure 3 C).…”

Cerebral Apolipoprotein D Exits the Brain and Accumulates in Peripheral Tissues

“…One possible interpretation is that ApoD could also participate in the elimination of harmful waste products (oxidized lipids) and pro-inflammatory molecules (ARA) from the CNS or other targeted tissues. ApoD is overexpressed in periods of neurodegenerative stress [15,[50][51][52][53][54][55]. ApoD is known to facilitate myelin clearance, extracellular matrix remodeling and axon regeneration after nerve injury [17].…”

“…ApoD can also limit inflammation and oxidative stress by reducing oxidized lipids [1,[9][10][11][12]. Because it is overexpressed during many neurodegenerative diseases and stresses, ApoD is considered an important factor in brain protection and repair [9,11,[13][14][15]. ApoD is also a member of the apolipoprotein family as it associates with lipoproteins (mainly high-density lipoproteins) in the blood.…”

Neuroprotective Effect of Apolipoprotein D in Cuprizone-Induced Cell Line Models: A Potential Therapeutic Approach for Multiple Sclerosis and Demyelinating Diseases

“…For example, Najyb et al (2017) demonstrated that hApo D internalization and accumulation in primary hippocampal neurons were accentuated by kainate treatment. In addition, these authors reported that hApo D could act by decreasing abnormally increased cholesterol levels in damaged neurons [ 68 ]. In this line, He et al (2009) showed that hApo D purified from BCF was able to bind arachidonic acid and cholesterol, attenuating the increase in oxidants and proinflammatory derivatives as F(2)-isoprostanes and 7-ketocholesterol in similar pathological conditions [ 69 ].…”