RESUMEN
Amyloidogenic processing of the amyloid precursor protein (APP) forms the amyloid-ß peptide (Aß) component of pathognomonic extracellular plaques of AD. Additional early cortical changes in AD include neuroinflammation and elevated iron levels. Activation of the innate immune system in the brain is a neuroprotective response to infection; however, persistent neuroinflammation is linked to AD neuropathology by uncertain mechanisms. Non-parametric machine learning analysis on transcriptomic data from a large neuropathologically characterised patient cohort revealed the acute phase protein lactoferrin (Lf) as the key predictor of amyloid pathology. In vitro studies showed that an interaction between APP and the iron-bound form of Lf secreted from activated microglia diverted neuronal APP endocytosis from the canonical clathrin-dependent pathway to one requiring ADP ribosylation factor 6 trafficking. By rerouting APP recycling to the Rab11-positive compartment for amyloidogenic processing, Lf dramatically increased neuronal Aß production. Lf emerges as a novel pharmacological target for AD that not only modulates APP processing but provides a link between Aß production, neuroinflammation and iron dysregulation.
Asunto(s)
Enfermedad de Alzheimer , Lactoferrina , Proteínas de Fase Aguda , Enfermedad de Alzheimer/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , HumanosRESUMEN
BACKGROUND: Type I collagen is the major component of the extracellular matrix of the knee's meniscus and plays a central role in that joint's biomechanical properties. Repair and reconstruction of tissue damage often requires a scaffold to assist the body to rebuild. The middle zone of bovine meniscus is a material that may be useful for the preparation of extracellular matrix scaffolds. METHODS: Here, synchrotron-based small-angle X-ray scattering (SAXS) patterns of bovine meniscus were collected during unconfined compression. Collagen fibril orientation, D-spacing, compression distance and force were measured. RESULTS: The collagen fibrils in middle zone meniscal fibrocartilage become more highly oriented perpendicular to the direction of compression. The D-spacing also increases, from 65.0 to 66.3 nm with compression up to 0.43 MPa, representing a 1.8% elongation of collagen fibrils perpendicular to the compression. CONCLUSION: The elasticity of the collagen fibrils under tension along their length when the meniscus is compressed, therefore, contributes to the overall elastic response of the meniscus only under loads that exceed those likely to be experienced physiologically.
Asunto(s)
Colágeno/química , Meniscos Tibiales/química , Meniscos Tibiales/fisiología , Animales , Fenómenos Biomecánicos , Bovinos , Colágeno/metabolismo , Colágeno Tipo I/química , Colágeno Tipo I/metabolismo , Elasticidad , Masculino , Dispersión del Ángulo Pequeño , Estrés Mecánico , Sincrotrones , Difracción de Rayos XRESUMEN
Alzheimer's disease (AD) is the most common cause of dementia in the elderly population and attempts to develop therapies have been unsuccessful because there is no means to target an effective therapeutic window. CNS biomarkers are insightful but impractical for high-throughput population-based screening. Therefore, a peripheral, blood-based biomarker for AD would significantly improve early diagnosis, potentially enable presymptomatic detection and facilitate effective targeting of disease-modifying treatments. The various constituents of blood, including plasma, platelets and cellular fractions, are now being systematically explored as a pool of putative peripheral biomarkers for AD. In this review we cover some less known peripheral biomarkers and highlight the latest developments for their clinical application.
