BACE1 and SCD1 are associated with neurodegeneration.

Introduction: Proteolytic processing of amyloid protein precursor by ß-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.

Factores asociados con el tiempo de progresión de la discapacidad en pacientes con esclerosis múltiple / Factors associated with time to disability progression in patients with multiple sclerosis

Objetivos. Determinar los factores sociodemográficos, clínicos y radiológicos asociados al tiempo de progresión de discapacidad en pacientes con esclerosis múltiple (EM). Materiales y métodos. Estudio transversal analítico, basado en registros de la historia clínica de pacientes del Instituto Neurológico de Colombia, entre el 2013 y 2021. La progresión a discapacidad de los pacientes con EM se definió como el tiempo hasta un aumento de por lo menos 0,5 puntos en el valor de la EDSS (del inglés Expanded Disability Status Scale), sostenido por al menos seis meses. Se usó un modelo de regresión de Cox para estimar la función de supervivencia y los hazard ratios (HR) con sus intervalos de confianza de 95% (IC 95%). Resultados. Se incluyeron 216 pacientes, de los cuales el 25% progresó a discapacidad, la mediana de supervivencia fue de 78 meses (RIC 95%: 70−83), las lesiones activas (HR = 1,94; IC 95%: 1,10−3,44), el sexo masculino (HR = 2,5; IC 95%: 1,32−4,73), y las enfermedades neurológicas (HR = 2,18; IC95%: 1,03−4,61) se asociaron en el modelo multivariado. Conclusiones. La mediana de tiempo de progresión hacia la discapacidad fue de 72 meses. Las lesiones activas captadas en resonancia magnética y el sexo masculino se asociaron con mayor progresión de la discapacidad, con resultados estadísticamente significativos en el modelo multivariado.

Objectives. To determine the sociodemographic, clinical and radiological factors associated with time to disability progression in patients with multiple sclerosis (MS). Materials and methods. Cross-sectional descriptive study with an analytical component, based on clinical records of patients at the Neurological Institute of Colombia, between 2013 and 2021. Progression to disability in MS patients was defined as the time to an increase of at least 0.5 points in the EDSS (Expanded Disability Status Scale) score, sustained for at least six months. A Cox regression model was used to estimate the survival function and Hazard Ratios (HR) with their 95% confidence intervals (95% CI). Results. We included 216 patients, of whom 25% progressed to disability, median survival was 78 months (95% CI: 70-83), active lesions (HR = 1.94; 95% CI: 1.10-3.44), cerebellar complications (HR = 2.03; 95% CI: 0. 99-4.16), being male (HR = 2.5; 95% CI: 1.32-4.73), and having neurological diseases (HR = 2.18; 95% CI: 1.03-4.61) were associated as risk factors. While relapsing remitting MS (HR = 0.63; 95% CI: 0.31-1.26) and age at diagnosis less than 40 years (HR = 0.96; 95% CI: 0.53-1.76) were associated as protective factors. Conclusions. Progression is affected by many factors, and there is no single independent factor.

Neurodegeneration and convergent factors contributing to the deterioration of the cytoskeleton in Alzheimer's disease, cerebral ischemia and multiple sclerosis (Review).

The cytoskeleton is the main intracellular structure that determines the morphology of neurons and maintains their integrity. Therefore, disruption of its structure and function may underlie several neurodegenerative diseases. This review summarizes the current literature on the tau protein, microtubule-associated protein 2 (MAP2) and neurofilaments as common denominators in pathological conditions such as Alzheimer's disease (AD), cerebral ischemia, and multiple sclerosis (MS). Insights obtained from experimental models using biochemical and immunocytochemical techniques highlight that changes in these proteins may be potentially used as protein targets in clinical settings, which provides novel opportunities for the detection, monitoring and treatment of patients with these neurodegenerative diseases.

Lasting metabolic effect of a high-fructose diet on global cerebral ischemia.

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.

Considering risk factors for the effectiveness of translational therapies in brain stroke.

Multiple studies on cerebral ischemia have been performed in animal models to propose different strategies of neuroprotection that mitigate either the early or late consequences of the disease. These therapies have been successful in reducing the volume of infarction, the proinflammatory cascade, and the amount of free radicals, as well as reversing markers of neurodegeneration, among other events. However, when those strategies are translated to clinical studies, their effectiveness is not reproduced. This review will focus on highlighting some of the main limitations of the animal models of stroke that lead to unsuccessful translational therapies and the common risk factors in humans that should be carefully considered in the experimental design of future studies to generate a more realistic spatiotemporal physiopathology and improve therapeutic efficacy in cerebral ischemia.

[Neurogenesis and gliogenesis modulation in cerebral ischemia by CDK5 RNAi-based therapy].

INTRODUCTION: Cerebral ischemia is the third cause of death risk in Colombia and the first cause of physical disability worldwide. Different studies on the silencing of the cyclin-dependent kinase 5 (CDK5) have shown that reducing its activity is beneficial in ischemic contexts. However, its effect on neural cell production after cerebral ischemia has not been well studied yet. OBJECTIVE: To evaluate CDK5 silencing on the production of neurons and astrocytes after a focal cerebral ischemia in rats. MATERIALS AND METHODS: We used 40 eight-week-old male Wistar rats. Both sham and ischemia groups were transduced at CA1 hippocampal region with an adeno-associated viral vector using a noninterfering (shSCRmiR) and an interfering sequence for CDK5 (shCDK5miR). We injected 50 mg/kg of bromodeoxyuridine intraperitoneally from hour 24 to day 7 post-ischemia. We assessed the neurological abilities during the next 15 days and we measured the immunoreactivity of bromodeoxyuridine (BrdU), doublecortin (DCX), NeuN, and glial fibrillary acid protein (GFAP) from day 15 to day 30 post-ischemia. RESULTS: Our findings showed that CDK5miR-treated ischemic animals improved their neurological score and presented increased BrdU+ cells 15 days after ischemia, which correlated with higher DCX and lower GFAP fluorescence intensities, and, although mature neurons populations did not change, GFAP immunoreactivity was still significantly reduced at 30 days post-ischemia in comparison with untreated ischemic groups. CONCLUSION: CDK5miR therapy generated the neurological recovery of ischemic rats associated with the induction of immature neurons proliferation and the reduction of GFAP reactivity at short and longterm post-ischemia.

Neurogenesis and gliogenesis modulation in cerebral ischemia by CDK5 RNAi-based therapy / Modulación de la neurogénesis y la gliogénesis en la isquemia cerebral mediante una terapia basada en la interferencia de CDK5

Abstract Introduction: Cerebral ischemia is the third cause of death risk in Colombia and the first cause of physical disability worldwide. Different studies on the silencing of the cyclin-dependent kinase 5 (CDK5) have shown that reducing its activity is beneficial in ischemic contexts. However, its effect on neural cell production after cerebral ischemia has not been well studied yet. Objective: To evaluate CDK5 silencing on the production of neurons and astrocytes after a focal cerebral ischemia in rats. Materials and methods: We used 40 eight-week-old male Wistar rats. Both sham and ischemia groups were transduced at CA1 hippocampal region with an adeno-associated viral vector using a noninterfering (shSCRmiR) and an interfering sequence for CDK5 (shCDK5miR). We injected 50 mg/kg of bromodeoxyuridine intraperitoneally from hour 24 to day 7 post-ischemia. We assessed the neurological abilities during the next 15 days and we measured the immunoreactivity of bromodeoxyuridine (BrdU), doublecortin (DCX), NeuN, and glial fibrillary acid protein (GFAP) from day 15 to day 30 post-ischemia. Results: Our findings showed that CDK5miR-treated ischemic animals improved their neurological score and presented increased BrdU+ cells 15 days after ischemia, which correlated with higher DCX and lower GFAP fluorescence intensities, and, although mature neurons populations did not change, GFAP immunoreactivity was still significantly reduced at 30 days post-ischemia in comparison with untreated ischemic groups. Conclusion: CDK5miR therapy generated the neurological recovery of ischemic rats associated with the induction of immature neurons proliferation and the reduction of GFAP reactivity at short and longterm post-ischemia.

Resumen Introducción. La isquemia cerebral es la tercera causa de riesgo de muerte en Colombia y la primera causa de discapacidad física en el mundo. En diversos estudios en los que se silenció la cinasa 5 dependiente de la ciclina (CDK5) se ha demostrado que la reducción de su actividad es beneficiosa frente a la isquemia. Sin embargo, su efecto sobre la neurogénesis después de la isquemia no se ha dilucidado suficientemente. Objetivo. Evaluar el silenciamiento de la CDK5 en la neurogénesis y la gliogénesis después de la isquemia cerebral focal en ratas. Materiales y métodos. Se usaron 40 machos de rata Wistar de ocho semanas de edad. Los grupos de control y los isquémicos sometidos a transducción en la región del hipocampo CA1, se inyectaron intraperitonealmente por estereotaxia con 50 mg/kg de bromodesoxiuridina (BrdU) a partir de las 24 horas y hasta el día 7 después de la isquemia, con un vector viral asociado a adenovirus usando una secuencia no interferente (SCRmiR) y una interferente (CDK5miR). Se evaluó la capacidad neurológica durante los quince días siguientes y se detectó la capacidad de inmunorreacción para la BrdU, la proteína doblecortina (DCX), los núcleos neuronales (NeuN), y la proteína fibrilar acídica de la glía (Glial Fibrillary Acidic Protein, GFAP) a los 15 y 30 días de la isquemia. Resultados. Los animales isquémicos tratados con CDK5miR mejoraron su puntuación neurológica y presentaron un incremento de la BrdU+ a los 15 días de la isquemia, lo cual se correlacionó con una mayor intensidad de la DCX+ y una menor de la GFAP+. No hubo modificación de los NeuN+, pero sí una reducción significativa de la GFAP+ a los 30 días de la isquemia en los animales tratados comparados con los animales isquémicos no tratados. Conclusión. La terapia con CDK5miR generó la recuperación neurológica de ratas isquémicas asociada con la inducción de la neurogénesis y el control de la capacidad de reacción de la proteína GFAP a corto y largo plazo después de la isquemia.

Diferenciación clínica del déficit cognitivo del CADASIL con respecto a otras demencias vasculares / Clinical differentiation of the cognitive deficit of CADASIL whit respect to the other vascular dementias

En el mundo hay unos 47 millones de personas que padecen demencia, y cada año se registran cerca de 10 millones de nuevos casos. La demencia es una de las principales causas de discapacidad y dependencia entre las personas mayores de 65 años. La demencia vascular constituye la segunda causa de demencia en adultos mayores y en ocasiones su diagnóstico es poco asertivo por la variedad y similitud de síntomas entre las diferentes enfermedades que originan demencia vascular, incluyendo CADASIL (acrónimo inglés de Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy); particularmente el déficit cognitivo es de los síntomas más complejos de diagnóstico, teniendo en cuenta que su manifestación clínica depende de la magnitud y localización de la lesión. La enfermedad de CADASIL, aunque se constituye como una infrecuente causa de demencia vascular de naturaleza hereditaria a nivel mundial, representa una patología de gran importancia en el ámbito nacional, dado que en familias colombianas se ha reportado mutaciones que conllevan a dicha patología. Por lo tanto, su diagnóstico y tratamiento constituyen un reto para el personal clínico, sabiendo que la identificación temprana y precisa es la mejor estrategia para evitar la progresión precoz de la enfermedad y el mejoramiento de la calidad de vida del paciente. De acuerdo con lo anterior, se realizó una revisión de la diferenciación clínica del déficit cognitivo del CADASIL con respecto a las demás demencias vasculares, con el fin de generar una herramienta que apoye la diferenciación clínica de dicha patología.

In the world, there are approximately 47 million people who have dementia, and every year they register near 10 million new cases. The dementia is one of the principal reasons for disability and dependence between people older than 65 years old. Vascular dementia constitutes the second reason of dementia in the elders, and sometimes the diagnosis is slightly assertive because of the variety and similarity of symptoms between the different diseases that originate vascular dementia, including CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy). Particularly, the cognitive deficit is one of the most complex symptoms of diagnosis, bearing in mind that its clinical manifestation depends on the magnitude and location of the injury. CADASIL disease, though it constituted as an infrequent reason of vascular dementia of hereditary nature worldwide, represents a pathology of great importance in the national area, because, in Colombian families, there have been reported mutations that carry to the above-mentioned pathology. Therefore, its diagnosis and treatment constitute a challenge for the clinical personnel, knowing that the early and precise identification is the best strategy to avoid the rapid progression of the disease and the improvement of the quality of life of the patient. In agreement with the previous information, there was made a review of the clinical differentiation of the cognitive deficit of CADASIL regarding other vascular dementias, to generate a tool that supports the clinical differentiation of the pathology mentioned above.

Perspective of synaptic protection after post-infarction treatment with statins.

Stroke is the second most common cause of death in people over 45 years of age in Colombia and is the leading cause of permanent disability worldwide. Cerebral ischemia is a stroke characterized by decreased blood flow due to the occlusion of one or more cerebral arteries, which can cause memory problems and hemiplegia or paralysis, among other impairments. The literature contains hundreds of therapies (invasive and noninvasive) that exhibit a neuroprotective effect when evaluated in animal models. However, in clinical trials, most of these drugs do not reproduce the previously demonstrated neuroprotective property, and some even have adverse effects that had not previously been detected in animal experimentation.Statins are drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis. Several studies have shown that statin therapy in an animal model of focal cerebral ischemia reduces infarct volume, as well as markers of neurodegeneration, activates neuronal survival pathways, and improves performance on learning and memory tests. Given the implied therapeutic benefit and the limited understanding of the mechanism of action of statins in brain repair, it is necessary to address the biochemical and tissue effects of these drugs on synaptic proteins, such as NMDA receptors, synaptic adhesion proteins, and cytoskeletal proteins; these proteins are highly relevant therapeutic targets, which, in addition to giving a structural account of synaptic connectivity and function, are also indicators of cellular communication and the integrity of the blood-brain barrier, which are widely affected in the long term post-cerebral infarct but, interestingly, are protected by statins when administered during the acute phase.

GluN2B N-methyl-D-aspartic acid receptor subunit mediates atorvastatin-Induced neuroprotection after focal 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.