Search

Introduction: Proteolytic processing of amyloid protein precursor by β-site secretase enzyme (BACE1) is dependent on the cellular lipid composition and is affected by endomembrane trafficking in dementia and Alzheimer's disease (AD). Stearoyl-CoA desaturase 1 (SCD1) is responsible for the synthesis of fatty acid monounsaturation (MUFAs), whose accumulation is strongly associated with cognitive dysfunction., Methods: In this study, we analyzed the relationship between BACE1 and SCD1 in vivo and in vitro neurodegenerative models and their association in familial AD (FAD), sporadic AD (SAD), and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) using microscopy, biochemical, and mass SPECT approach., Results: Our findings showed that BACE1 and SCD1 immunoreactivities were increased and colocalized in astrocytes of the hippocampus in a rat model of global cerebral ischemia (2-VO). A synergistic effect of double BACE1/SCD1 silencing on the recovery of motor and cognitive functions was obtained. This neuroprotective regulation involved the segregation of phospholipids (PLs) associated with polyunsaturated fatty acids in the hippocampus, cerebrospinal fluid, and serum. The double silencing in the sham and ischemic groups was stronger in the serum, inducing an inverse ratio between total phosphatydilcholine (PC) and lysophosphatidylcholine (LPC), represented mainly by the reduction of PC 38:4 and PC 36:4 and an increase in LPC 16:0 and LPC 18:0. Furthermore, PC 38:4 and PC:36:4 levels augmented in pathological conditions in in vitro AD models. BACE1 and SCD1 increases were confirmed in the hippocampus of FAD, SAD, and CADASIL., Conclusion: Therefore, the findings suggest a novel convergence of BACE-1 and SCD1 in neurodegeneration, related to pro-inflammatory phospholipids., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bedoya-Guzmán, Pacheco-Herrero, Salomon-Cruz, Barrera-Sandoval, Gutierrez Vargas, Villamil-Ortiz, Villegas Lanau, Arias-Londoño, Area-Gomez and Cardona Gomez.)

Objectives: Cerebral ischemia is the most common cause of disability, the second most common cause of dementia, and the fourth most common cause of death in the developed world [Sveinsson OA, Kjartansson O, Valdimarsson EM. Heilablóðþurrð/heiladrep: Faraldsfræði, orsakir og einkenni [Cerebral ischemia/infarction - epidemiology, causes and symptoms]. Laeknabladid. 2014 May;100(5):271-9. Icelandic. doi:10.17992/lbl.2014.05.543]. Obesity has been associated with worse outcomes after ischemia in rats, triggering proinflammatory cytokine production related to the brain microvasculature. The way obesity triggers these effects remains mostly unknown. Therefore, the aim of this study was to elucidate the cellular mechanisms of damage triggered by obesity in the context of cerebral ischemia., Methods: We used a rat model of obesity induced by a 20% high fructose diet (HFD) and evaluated peripheral alterations in plasma (lipid and cytokine profiles). Then, we performed cerebral ischemia surgery using two-vessel occlusion (2VO) and analyzed neurological/motor performance and glial activation. Next, we treated endothelial cell line cultures with glutamate in vitro to simulate an excitotoxic environment, and we added 20% plasma from obese rats. Subsequently, we isolated EVs released from endothelial cells and treated primary cultures of astrocytes with them., Results: Rats fed a HFD had an increased BMI with dyslipidemia and high levels of proinflammatory cytokines. Glia from the obese rats exhibited altered morphology, suggesting hyperreactivity related to neurological and motor deficits. Plasma from obese rats induced activation of endothelial cells, increasing proinflammatory signals and releasing more EVs. Similarly, these EVs caused an increase in NF-κB and astrocyte cytotoxicity. Together, the results suggest that obesity activates proinflammatory signals in endothelial cells, resulting in the release of EVs that simultaneously contribute to astrocyte activation.

Introduction : Obesity is a public health problem that is associated with cerebrovascular diseases, such as ischemic stroke. The coexistence of obesity with cerebral ischemia has been suggested to be considerably detrimental to the neurological system. Objective : Hence, in this study, we evaluated the long-term effects of a 20% high fructose diet (HFD) and global cerebral ischemia on neurological, cognitive and emotional performance in three-month-old male Wistar rats. Results : Our results demonstrated that fructose intake led to increases in body weight and blood glucose, as well as reduced insulin sensitivity. The co-morbidity of fructose intake and cerebral ischemia resulted to hyperlipidemia, as well as increases in liver and adipocyte damage, which worsened neurological performance and resulted in alterations in learning and emotional skills at two weeks post-ischemia. No significant biochemical changes in autophagy and plasticity markers at the late stage of ischemia were observed. Conclusion : These results suggested that obesity causes a lasting effect on metabolic disorders that can contribute to increased neurological impairment after cerebral ischemia.

Statins are potent cholesterol biosynthesis inhibitors that exert protective effects in humans and in experimental models of stroke. The mechanisms involved in these protective actions are not completely understood. This study evaluates whether atorvastatin (ATV) treatment affects the GluN1 and GluN2B subunits of the N-methyl-D-aspartic acid receptor in the somatosensory cerebral cortex at short and long periods following ischemia. Sham and ischemic male Wistar rats received 10 mg/kg of ATV or placebo by gavage every 24 hr for 3 consecutive days. The first dose was administered 6 hr after ischemia-reperfusion or the sham operation. ATV treatment resulted in faster recovery of neurological scores than placebo, prevented the appearance of pyknotic neurons, and restored microtubule-associated protein 2 and neuronal nuclei staining to control values in the somatosensory cerebral cortex and the hippocampus at 72 hr and 15 days postischemia. Furthermore, ATV prevented spatial learning and memory deficits caused by cerebral ischemia. Cerebral ischemia reduced the number of GluN1/PSD-95 and GluN2B/PSD-95 colocalization clusters in cortical pyramidal neurons and reduced the levels of brain-derived neurotrophic factor (BDNF) in the cerebral cortex. These effects of the ischemic insult were prevented by ATV, which also induced GluN2B/PSD-95 colocalization in neuronal processes and an association of GluN2B with TrkB. The GluN2B pharmacological inhibitor ifenprodil prevented the increase in BDNF levels and the motor and cognitive function recovery caused by ATV in ischemic rats. These findings indicate that GluN2B is involved in the neuroprotective mechanism elicited by ATV to promote motor and cognitive recovery after focal cerebral ischemia., (Copyright © 2014 Wiley Periodicals, Inc.)