Proteína precursora del beta-amiloide (ß-App) y daño axonal difuso tras un traumatismo craneoencefálico: un punto de vista forense / Beta-amiloid precursos protein (ß-App) and diffuse axonal damage after head injuries: a forensic point of view

Resumen La proteína precursora del β- Amiloide (β-APP) es una glicoproteína de membrana y un componente habitual de las neuronas. Tiene funciones en el crecimiento y la adhesión celular tras un traumatismo. Es transportada mediante transporte rápido axonal anterógrado y se acumula dentro de las neuronas cuando se daña citoesqueleto. Este proceso es activo, es decir consume energía. El β-APP no es específico de los traumatismos. Se acumula en cualquier circunstancia en la que se dañen los axones, tal como la hipoxia, alteraciones metabólicas, y cualquier otra causa de edema cerebral y aumento de la presión intracraneal que puedan conducir a un daño axonal difuso (DAI) En el presente estudio estudiamos la expresión de esta proteína en casos de traumatismo cráneo-encefálico con diferente evolución cronológica El daño del citoesqueleto producido por la proteólisis, junto con la alteración de las quinasas y las fosfatasas, aumentan la permeabilidad de la membrana, lo que provoca la entrada de calcio en la célula que, a su vez, activa la calmodulina que hace que los neurofilamentos se compacten, los microtúbulos desaparezcan y se rompa la espectrina. Esta disrupción del citoesqueleto tiene como consecuencia que las sustancias que se transportan a su través, se acumulen, sobre todo en las zonas afectadas por el DAI. Al final de todo este proceso, los axones se rompen, lo que se conoce como axotomía secundaria. El estudio de la acumulación del β-APP es útil para valorar la extensión del DAI y para determinar el tiempo de supervivencia tras el traumatismo o cualquier otro daño cerebral.

Abstract β-Amyloid Precursor Protein (β-APP) is a membrane glycoprotein and a common component of neurons. It is involved in adhesion and cell growth processes after traumatic events. It is carried by anterograde fast axonal transport, and it accumulates inside neurons when the cytoskeleton is damaged. This is a vital biochemical process that consumes energy. β-APP is not specific of traumatic events. It accumulates in any case of axonal damage, whatever its cause may be, like hypoxia, metabolic disorders, and any other circumstances that lead to brain swelling and intracranial pressure rising and in consequence to Diffuse Axonal Injury (DAI). In this study we review the expression of this protein in cases of traumatic brain injury with different chronological evolution. The damage of cytoskeleton due to proteolysis in addition to the disturbance of kinases and phosphatases increase the permeability of the membrane. Calcium gets into the cell and activates calmodulin, thus neurofilaments compact, microtubules disappear and spectrin breaks. This disruption of the cytoskeleton has as consequence that the transported substances accumulate in the most affected areas by DAI. At the end of this process axon breaks, which is known as secondary axotomy. The study of the accumulation of β-APP is useful to assess the extent of DAI and to determine the time elapsed after trauma or another insult to CNS.

Cerebral amyloid angiopathy: a cross-sectional study in a single center in Northeastern Brazil / Angiopatia amiloide cerebral: um estudo transversal em um único centro no Nordeste brasileiro

ABSTRACT Background: Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder caused by progressive deposition of β-amyloid peptides in the walls of small and medium-sized cortical and leptomeningeal vessels. Until today, the prevalence of CAA is unknown in our region. Objective: This study aims to analyze the prevalence of this entity in a specific elderly population in a tertiary hospital in Northeastern Brazil. Methods: A cross-sectional, retrospective study with the enrollment of patients aged 65 or older followed in the neurological outpatient service of the Universidade Federal do Piauí, Brazil, who underwent brain magnetic resonance imaging (MRI) from July 2016 to June 2018. Results: One hundred and seventy-four patients were enrolled, of whom 100 were women (57.4%) and 74, men (42.6%), aged from 65 to 91 years old (median age 73.27). Nine patients were excluded from the study due to unavailability of MRI sequences needed for an appropriate analysis. Out of the 165 remaining patients, 12 (7.2%) had established the diagnosis of CAA, according to the modified Boston criteria. Conclusion: The prevalence of CAA in our study was like those of medical literature, with a progressive age-related increase.

RESUMO Introdução: A angiopatia amiloide cerebral (AAC) é uma desordem vascular causada pela deposição progressiva de peptídeos β-amiloides nas paredes de pequenos e médios vasos corticais e leptomeníngeos. Até a presente data, a epidemiologia da AAC é desconhecida em nossa região. Objetivos: Avaliar a prevalência da AAC em uma população específica de pacientes idosos de um hospital terciário no nordeste brasileiro. Métodos: Estudo transversal, retrospectivo, com seleção de pacientes com idade igual ou superior a 65 anos, acompanhados no serviço de Neurologia do Hospital Universitário da Universidade Federal do Piauí, Brasil, e que foram submetidos a exame de ressonância nuclear magnética entre julho de 2016 e junho de 2018. Resultados: Foram recrutados 174 pacientes, dos quais 100 eram mulheres (57,4%) e 74 homens (42,6%), com idades entre 65 e 91 anos (média de 73,27). Nove pacientes foram excluídos devido à indisponibilidade de sequências de ressonância magnética necessárias para uma análise apropriada. Dos 165 pacientes restantes, 12 (7,2%) foram diagnosticados com AAC de acordo com os critérios de Boston modificados. Conclusão: A prevalência da AAC em nosso estudo foi semelhante ao resultado encontrado na literatura médica, com um aumento progressivo relacionado à idade.

Conformational study of N-methylated alanine peptides and design of Aẞ inhibitor.

N-Methylation increases the proteolytic stability of peptides and leads to improved pharmacological and increased nematicidal property against plant pathogens. In this study, the quantum mechanical and molecular dynamic simulation approaches were used to investigate conformational behavior of peptides containing only N-methylated alanine (NMeAla) residues and N-methylated alanine and alanine residues at alternate positions. The amide bond geometry was found to be trans and the poly NMeAla peptides were shown to populate in the helical structure without hydrogen bond with , values of ~ 0, 90˚ stabilized by carbonyl-carbonyl interactions. Molecular dynamic simulations in water/methanol revealed the formation of β-strand structure, irrespective of the starting geometry due to the interaction of solvent molecules with the carbonyl groups of peptide backbone. Analysis of simulation results as a function of time suggested that the opening of helical structure without hydrogen bond started from C-terminal. Conformational behavior of peptides containing N-MeAla and Ala was used to design Ab peptide inhibitor and the model tetrapeptide Ac-Ala-NMeAla-Ala-NHMe in the β-strand structure was shown to interact with the hydrophobic stretch of Aβ15-42 peptide.

Intracellular amyloid beta interacts with SOD1 and impairs the enzymatic activity of SOD1: implications for the pathogenesis of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by the degeneration of motor neurons. Mutations in Cu/Zn superoxide dismutase (SOD1), including G93A, were reportedly linked to familial ALS. SOD1 is a key antioxidant enzyme, and is also one of the major targets for oxidative damage in the brains of patients suffering from Alzheimer's disease (AD). Several lines of evidence suggest that intracellular amyloid beta (Abeta) is associated with the pathogenesis of AD. In this report we demonstrate that intracellular Abeta directly interacts with SOD1, and that this interaction decreases the enzymatic activity of the enzyme. We observed Abeta-SOD1 aggregates in the perinuclear region of H4 cells, and mapped the SOD1 binding region to Abeta amino acids 26-42. Interestingly, intracellular Abeta binds to the SOD1 G93A mutant with greater affinity than to wild-type SOD1. This resulted in considerably less mutant enzymatic activity. Our study implicates a potential role for Abeta in the development of ALS by interacting with the SOD1 G93A mutant.