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


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 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.

Establishment of a reproducible and minimally invasive ischemic stroke model in swine

Carlos Castaño Marc Melià-Sorolla Alexia García-Serran et al. JCI Insight 2023. Apr 24;8(8):e163398. doi: 10.1172/jci.insight.163398. PMID: 36853828

Abstract: The need for advances in the management/treatment options for ischemic stroke patients requires that upcoming preclinical research uses animals with more human-like brain characteristics. The porcine brain is considered appropriate, although the presence of the rete mirabile (RM) prevents direct catheterization of the intracranial arteries to produce focal cerebral ischemia. To develop a reproducible minimally invasive porcine stroke model, a guide catheter and guide wire were introduced through the femoral artery until reaching the left RM. Using the pressure cooker technique, Squid-12 embolization material was deposited to fill, overflow, and occlude the left RM, the left internal carotid artery, and left circle of Willis wing up to the origins of the middle cerebral arteries (MCAs), mimicking the occlusion produced in the filament model in rodents. Longitudinal multimodal cerebral MRI was conducted to assess the brain damage and cerebral blood supply. The technique we describe here occluded up to the origins of the MCAs in 7 of 8 swine, inducing early damage 90 minutes after occlusion that later evolved to a large cerebral infarction and producing no mortality during the intervention. This minimally invasive ischemic stroke model in swine produced reproducible infarcts and shows translational features common to human stroke.

Funding: This academic research was supported by grants from the Fondo de Investigaciones Sanitarias-Instituto de Salud Carlos III PI18/01813 and PI21/01925 to AD and TG, INVICTUS PLUS RD16/0019/0020 and RICORS RD21/0006/0024 that was susceptible to be cofinanced by FEDER/FSE funds, and grants from Agency for Management of University and Research Grants (AGAUR) Catalan Research Group (SGR) 2017SGR1520, 2021SGR00925, and 2019PROD00120 susceptible to be cofinanced by FEDER funds. MMS was supported by a PFIS contract of the ISCIII (FI19/00174), and AGS was supported by contracts associated to 2019PROD00120 and PI18/01813. The IGTP is a Research Center of Catalonia of the CERCA Program/government of Catalonia. The group has received funding from “la Caixa” CI15-00009; from the European Institute of Innovation and Technology (EIT) PoC-2016-SPAIN-04, which receives support from the European Union’s Horizon 2020 research and innovation program; and from the Fundación para la Innovación y la Prospectiva en Salud en España (FIPSE) program 3594-18.