Publicaciones

Dihydropyrimidinase-Related Protein 2 Is a New Partner in the Binding between 4E-BP2 and eIF4E Related to Neuronal Death after Cerebral Ischemia

Martínez-Alonso E, Escobar-Peso A, Guerra-Pérez N et al. Int J Mol Sci. 2023 May 4;24(9):8246. doi: 10.3390/ijms24098246. PMID: 37175950

https://pubmed.ncbi.nlm.nih.gov/37175950/

Abstract: Transient cerebral ischemia induces neuronal degeneration, followed in time by secondary delayed neuronal death that is strongly correlated with a permanent inhibition of protein synthesis in vulnerable brain regions, while protein translational rates are recovered in resistant areas. In the translation-regulation initiation step, the eukaryotic initiation factor (eIF) 4E is a key player regulated by its association with eIF4E-binding proteins (4E-BPs), mostly 4E-BP2 in brain tissue. In a previous work, we identified dihydropyrimidinase-related protein 2 (DRP2) as a 4E-BP2-interacting protein. Here, using a proteomic approach in a model of transient cerebral ischemia, a detailed study of DRP2 was performed in order to address the challenge of translation restoration in vulnerable regions. In this report, several DRP2 isoforms that have a specific interaction with both 4E-BP2 and eIF4E were identified, showing significant and opposite differences in this association, and being differentially detected in resistant and vulnerable regions in response to ischemia reperfusion. Our results provide the first evidence of DRP2 isoforms as potential regulators of the 4E-BP2–eIF4E association that would have consequences in the delayed neuronal death under ischemic-reperfusion stress. The new knowledge reported here identifies DRP2 as a new target to promote neuronal survival after cerebral ischemia. 

Funding: This study has been funded by Instituto de Salud Carlos III and cofunded by European Regional Development Fund (ERDF, “A way to make Europe”) through the projects PI18/00255, PI22/01381 and RICORS RD21/0006/0019 to J.M. and A.A.

Association of candidate genetic variants and circulating levels of ApoE/ApoJ with common neuroimaging features of cerebral amyloid angiopathy

Bonaterra-Pastra A, Benítez S, Pancorbo O et al. Front Aging Neurosci. 2023 Apr 11;15:1134399. doi: 10.3389/fnagi.2023.1134399. eCollection 2023. PMID: 37113571

https://pubmed.ncbi.nlm.nih.gov/37113571/

Abstract:

Introduction: Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid-β (Aβ) in brain vessels and is a main cause of lobar intracerebral hemorrhage (ICH) in the elderly. CAA is associated with magnetic resonance imaging (MRI) markers of small vessel disease (SVD). Since Aβ is also accumulated in Alzheimer’s disease (AD) in the brain parenchyma, we aimed to study if several single nucleotide polymorphisms (SNPs) previously associated with AD were also associated with CAA pathology. Furthermore, we also studied the influence of APOE and CLU genetic variants in apolipoprotein E (ApoE) and clusterin/apolipoprotein J (ApoJ) circulating levels and their distribution among lipoproteins.
Methods: The study was carried out in a multicentric cohort of 126 patients with lobar ICH and clinical suspicion of CAA.
Results: We observed several SNPs associated with CAA neuroimaging MRI markers [cortical superficial siderosis (cSS), enlarged perivascular spaces in the centrum semiovale (CSO-EPVS), lobar cerebral microbleeds (CMB), white matter hyperintensities (WMH), corticosubcortical atrophy and CAA-SVD burden Frontiers in Aging Neuroscience 01 frontiersin.org Bonaterra-Pastra et al. 10.3389/fnagi.2023.1134399 score]. Concretely, ABCA7 (rs3764650), CLU (rs9331896 and rs933188), EPHA1 (rs11767557), and TREML2 (rs3747742) were significantly associated with a CAASVD burden score. Regarding circulating levels of apolipoproteins, protective AD SNPs of CLU [rs11136000 (T) and rs9331896 (C)] were significantly associated with higher HDL ApoJ content in the lobar ICH cohort. APOEε2 carriers presented higher plasma and LDL-associated ApoE levels whereas APOEε4
carriers presented lower plasma ApoE levels. Additionally, we observed that lower circulating ApoJ and ApoE levels were significantly associated with CAA-related MRI markers. More specifically, lower LDL-associated ApoJ and plasma and HDLassociated ApoE levels were significantly associated with CSO-EPVS, lower ApoJ content in HDL with brain atrophy and lower ApoE content in LDL with the extent of cSS.
Discussion: This study reinforces the relevance of lipid metabolism in CAA and cerebrovascular functionality. We propose that ApoJ and ApoE distribution among lipoproteins may be associated with pathological features related to CAA with higher ApoE and ApoJ levels in HDL possibly enhancing atheroprotective, antioxidative, and anti-inflammatory responses in cerebral β-amyloidosis.

Funding: This work was funded by the Instituto de Salud Carlos III (ISCIII), (PI17/00275, PI019/00421, PI20/00465, and PI20/00334) and co-financed by the European Regional Development Fund (FEDER). The Neurovascular Research Laboratory was part of the RICORS-ICTUS-Enfermedades Vasculares Cerebrales Network, ISCIII, Spain (RD21/0006/0007). CIBERDEM (CB07/08/0016) was an ISCIII Project.