Phagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer's disease

Reactive astrogliosis, a complex process characterized by cell hypertrophy and upregulation ofcomponents of intermediate filaments, is a common feature in brains of Alzheimer’s patients. Reac-tive astrocytes are found in close association with neuritic plaques; however, the precise role ofthese glial cells in disease pathogenesis is unknown. In this study, using immunohistochemical tech-niques and light and electron microscopy, we report that plaque-associated reactive astrocytesenwrap, engulf and may digest presynaptic dystrophies in the hippocampus of amyloid precursorprotein/presenilin-1 (APP/PS1) mice. Microglia, the brain phagocytic population, was apparentlynot engaged in this clearance. Phagocytic reactive astrocytes were present in 35% and 67% ofamyloid plaques at 6 and 12 months of age, respectively. The proportion of engulfed dystrophicneurites was low, around 7% of total dystrophies around plaques at both ages. This fact, alongwith the accumulation of dystrophic neurites during disease course, suggests that the efficiency ofthe astrocyte phagocytic process might be limited or impaired. Reactive astrocytes surroundingand engulfing dystrophic neurites were also detected in the hippocampus of Alzheimer’spatientsby confocal and ultrastructural analysis. We posit that the phagocytic activity of reactive astrocytesmight contribute to clear dysfunctional synapses or synaptic debris, thereby restoring impairedneural circuits and reducing the inflammatory impact of damaged neuronal parts and/or limitingthe amyloid pathology. Therefore, potentiation of the phagocytic properties of reactive astrocytesmay represent a potential therapy in Alzheimer s disease.Fondo de Investigación Sanitaria (FIS). Instituto de Salud Carlos III (ISCiii) de España y fondos FEDER de la Unión Europea. PI15/00796 y PI15/00957Fundación La Marató-TV3 de Cataluña, España. 20141432, 20141431, 20141433, y 20141430Centro de investigación en red de enfermedades neurodegenerativas (CIBERNED) de España. PI2015-2/02Junta de Andalucía. Proyecto de Excelencia CTS-203

Defective lysosomal proteolysis and axonal transport are early pathogenic events that worsen with age leading to increased APP metabolism and synaptic Abeta in transgenic APP/PS1 hippocampus

Background: Axonal pathology might constitute one of the earliest manifestations of Alzheimer disease. Axonal dystrophies were observed in Alzheimer’s patients and transgenic models at early ages. These axonal dystrophies could reflect the disruption of axonal transport and the accumulation of multiple vesicles at local points. It has been also proposed that dystrophies might interfere with normal intracellular proteolysis. In this work, we have investigated the progression of the hippocampal pathology and the possible implication in Abeta production in young (6 months) and aged (18 months) PS1(M146L)/APP(751sl) transgenic mice. Results: Our data demonstrated the existence of a progressive, age-dependent, formation of axonal dystrophies, mainly located in contact with congophilic Abeta deposition, which exhibited tau and neurofilament hyperphosphorylation. This progressive pathology was paralleled with decreased expression of the motor proteins kinesin and dynein. Furthermore, we also observed an early decrease in the activity of cathepsins B and D, progressing to a deep inhibition of these lysosomal proteases at late ages. This lysosomal impairment could be responsible for the accumulation of LC3-II and ubiquitinated proteins within axonal dystrophies. We have also investigated the repercussion of these deficiencies on the APP metabolism. Our data demonstrated the existence of an increase in the amyloidogenic pathway, which was reflected by the accumulation of hAPPfl, C99 fragment, intracellular Abeta in parallel with an increase in BACE and gamma-secretase activities. In vitro experiments, using APPswe transfected N2a cells, demonstrated that any imbalance on the proteolytic systems reproduced the in vivo alterations in APP metabolism. Finally, our data also demonstrated that Abeta peptides were preferentially accumulated in isolated synaptosomes. Conclusion: A progressive age-dependent cytoskeletal pathology along with a reduction of lysosomal and, in minor extent, proteasomal activity could be directly implicated in the progressive accumulation of APP derived fragments (and Abeta peptides) in parallel with the increase of BACE-1 and gamma-secretase activities. This retard in the APP metabolism seemed to be directly implicated in the synaptic Abeta accumulation and, in consequence, in the pathology progression between synaptically connected regions

¿Qué sueñan los ciegos?

A question whose answer, at first glance, might seem easy, has been the subject of intense debate for a long time among so-called cognitive neuroscientists. If we are talking about congenital blindness (blind from birth), the most reasonable answer would be that the dreams of these people would be imbued with tactile, auditory, and even kinesthetic (sense of movement) sensations, but lacking in visual contentUna pregunta cuya respuesta, a priori, podría parecer fácil, ha sido motivo de intenso debate durante largo tiempo entre los denominados neurocientíficos cognitivos. Si estamos hablando de ceguera congénita (ciegos de nacimiento), la respuesta más razonable sería que los sueños de dichas personas estarían impregnados de sensaciones táctiles, auditivas e incluso cinestésicas (sensación de movimiento), pero carentes de contenido visua