Peripheral myeloid cells infiltrate the hippocampus of Alzheimer's disease patients.

Microglia, the brain-resident myeloid cells, play a major role in the immune responses of the nervous system and in the pathogenesis of Alzheimer's disease (AD). However, the presence of peripheral myeloid cells in the AD brains remain to be demonstrated. Cellular and molecular approaches have been carried out in post-mortem hippocampal samples from patients with AD and age-matched controls without neurological symptoms. Our study provides evidence that circulating monocytes infiltrate the AD brains. Our findings showed that a high proportion of demented cases was associated with up-regulation of genes rarely expressed by microglial cells and abundant in monocytes-derived cells (MDC), among which stands the scavenger receptor Cd163. These Cd163-positive MDC invaded the brain parenchyma, acquired a microglial-like morphology, and were located in close proximity to blood vessels. These cells infiltrated the nearby amyloid plaques contributing to plaque-associated myeloid cell heterogeneity. Besides, control individuals with high amyloid pathology, showed no signs of MDC brain infiltration or plaque invasion. The MDC infiltration was associated with the progression and severity of AD pathology.These results reveal the co-existence of distinct myeloid populations associated with amyloid plaques during disease progression, as well their region-specific contribution to neuroimmune protection. The recruitment of monocytes could be a consequence rather than the cause of the severity of the disease. Whether monocyte infiltration is beneficial or detrimental to AD pathology remains to be fully elucidated. These findings open the opportunity to design targeted therapies, not only to microglia, but also to peripheral immune cell population to modulate amyloid pathology and provide a better understanding of the immunological mechanisms underlying AD progression.Supported by ISCiii grants(PI21-0915(AG),PI21-00914(JV)co-financed by FEDER funds from European Union;Junta de Andalucia grants P18-RT-2233(AG) and US-1262734(JV)co-financed by Programa Operativo FEDER 2014-2020;PPIT.UMA.B1-2019-07(ESM). Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Mitochondrial ultrastructural defects in reactive astrocytes of Alzheimer's mice hippocampus.

Alzheimer's disease (AD) is a complex neurodegenerative condition that causes progressive memory loss and dementia. In AD brains astrocyte become reactive potentially contributing to cognitive decline. Astrocyte reactivity is a highly complex phenomenon with remarkable morphologic and molecular phenotype changes, and the role of astrocytes in the development of AD is still unknown. Astrocytes are the prevalent glial cells in the brain and have a large number of functions aimed at maintaining brain homeostasis including regulation of brain energy metabolism, maintenance of the blood-brain barrier, ion homeostasis, synaptic activity and plasticity, among many other functions. Any disruption regarding the normal roles of astrocytes can result in morphological and functional changes that ensue in pathological consequences. Mitochondrial dysfunction is an early event in the pathogenesis of AD, although most studies have focused on neurons and little is known about the functional characteristics and the dynamics of astrocyte mitochondria. We had performed an ultrastructural analysis using transmission electron microscopy in the hippocampus of amyloidogenic (APP/PS1) and tauopathy (P301S) mice. Our results show structural alterations in mitochondria that include double membrane rupture, cristae loss, and fragmentation together with a loss of their circularity. Since mitochondrial morphology is directly related to mitochondrial fusion/fission processes, the ultrastructural changes observed in astrocyte mitochondria in these amyloidogenic and tauopathy models suggest dynamic abnormalities in these organelles that may lead to deficits in astroglial function compromising their capability to maintain brain homeostasis and support neuronal energy metabolism and survival. A better understanding of cell type-specific mitochondrial dysfunction as a pathological feature of AD might hold great potential for the exploration of novel molecular targets for therapeutic development.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Involvement of different aβ-associated myeloid populations in the human alzheimer’s brain

Parenchymal microglia, the brain-resident immune cells, have been postulated as a critical factor in Alzheimer´s disease (AD) since the identification of genetic risk factors related to their functions. Though the role of microglia in the AD progression/development is still unknown, a dysfunctional response has recently gained support. However, the different phenotypes and the implication of others myeloid cells in the human pathology have not been determined yet. In this work, we analyzed the phenotypic profile displayed by damage-associated myeloid cells in two AD vulnerable brain regions, the frontal cortex and hippocampus. For this purpose, immunohistochemistry and image analysis approaches have been carried out in postmortem brain samples from patients with AD (Braak VVI stage) and aged controls without neurological symptoms (Braak 0-II stage). Damage-associated microglial cells were clustered around amyloid plaques and expressed Iba1, CD32,TMEM119, CD68,Trem2 and CD45high. A subset of these cells also expressed ferritin and Gal-3. However, and even though some Braak II individuals accumulated reactive CD45 and CD68-positive plaques, only AD patients exhibited parenchymal infiltration of CD163-positive monocyte-derived cells that invaded plaque near blood vessels. While the frontal cortex showed strong microglial activation similar to that reported in amyloidogenic mice, the hippocampus of the same patients showed an attenuated microglial activation with a degenerative phenotype. These results reveal the co-existence of distinct myeloid populations associated with amyloid plaques during disease progression, as well their region-specific contribution to neuroimmune protection. These findings open the opportunity to design targeted therapies, not only to microglia, but also to the population of macrophages to modulate amyloid pathology and provide a better understanding of the immunological mechanisms underlying AD progression.Supported by ISCiii grants (PI21-0915 (AG), PI21-00914 (JV)); FEDER funds from European Union, by Junta de Andalucia grants (P18-RT-2233 (AG), US-1262734 (JV)); Programa Operativo FEDER 2014-2020, and by grant PPIT.UMA.B1-2019-07 (ESM). Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Types and Distribution of Bioactive Polyunsaturated Aldehydes in a Gradient from Mesotrophic to OligotrophicWaters in the Alborán Sea (Western Mediterranean)

Polyunsaturated aldehydes (PUAs) are bioactive molecules suggested as chemical defenses and infochemicals. In marine coastal habitats, diatoms reach high PUA production levels during bloom episodes. Two fractions of PUA can usually be analyzed: pPUA obtained via artificial breakage of collected phytoplankton cells and dissolved PUA already released to the environment (dPUA). In nature, resource supply arises as a main environmental controlling factor of PUA production. In this work, we monitored the vertical distribution and daily variation of pPUA associated with large-size phytoplankton and dPUA, at three sites located in the Alboran Sea from mesotrophic to oligotrophic waters. The results corroborate the presence of large-size PUA producers in oligotrophic and mesotrophic waters with a significant (58%-85%) diatom biomass. In addition to diatoms, significant correlations between pPUA production and dinoflagellate and silicoflagellate abundance were observed. 2E,4E/Z-Heptadienal was the most abundant aldehyde at the three sites with higher values (17.1 fg center dot cell(-1)) at the most oligotrophic site. 2E,4E/Z-Decadienal was the least abundant aldehyde, decreasing toward the oligotrophic site. For the first time, we describe the daily fluctuation of pPUA attributable to cellular physiological state and not exclusively to taxonomical composition. Our results demonstrate the persistence of threshold levels of dPUA deep in the water column, as well as the different chromatographic profiles of dPUA compared with pPUA. We propose different isomerization processes that alter the chemical structure of the released PUAs with unknown effects on their stability, biological function, and potential bioactivity

Plaque-Associated Oligomeric Amyloid-Beta Drives Early Synaptotoxicity in APP/PS1 Mice Hippocampus: Ultrastructural Pathology Analysis

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by initial memory impairments that progress to dementia. In this sense, synaptic dysfunction and loss have been established as the pathological features that best correlate with the typical early cognitive decline in this disease. At the histopathological level, post mortem AD brains typically exhibit intraneuronal neurofibrillary tangles (NFTs) along with the accumulation of amyloid-beta (Abeta) peptides in the form of extracellular deposits. Specifically, the oligomeric soluble forms of Abeta are considered the most synaptotoxic species. In addition, neuritic plaques are Abeta deposits surrounded by activated microglia and astroglia cells together with abnormal swellings of neuronal processes named dystrophic neurites. These periplaque aberrant neurites are mostly presynaptic elements and represent the first pathological indicator of synaptic dysfunction. In terms of losing synaptic proteins, the hippocampus is one of the brain regions most affected in AD patients. In this work, we report an early decline in spatial memory, along with hippocampal synaptic changes, in an amyloidogenic APP/PS1 transgenic model. Quantitative electron microscopy revealed a spatial synaptotoxic pattern around neuritic plaques with significant loss of periplaque synaptic terminals, showing rising synapse loss close to the border, especially in larger plaques. Moreover, dystrophic presynapses were filled with autophagic vesicles in detriment of the presynaptic vesicular density, probably interfering with synaptic function at very early synaptopathological disease stages. Electron immunogold labeling showed that the periphery of amyloid plaques, and the associated dystrophic neurites, was enriched in Abeta oligomers supporting an extracellular location of the synaptotoxins. Finally, the incubation of primary neurons with soluble fractions derived from 6-month-old APP/PS1 hippocampus induced significant loss of synaptic proteins, but not neuronal death. Indeed, this preclinical transgenic model could serve to investigate therapies targeted at initial stages of synaptic dysfunction relevant to the prodromal and early AD.Instituto de Salud Carlos III (ISCiii) FEDER funds PI18/01557 and PI18/01556Junta de Andalucia UMA18-FEDERJA-211, P18-RT-2233 and US-126273Spanish Minister of Science and Innovation PID2019-108911RA-100, PID2019-107090RA-I00 and RYC-2017-21879Malaga University B1-2019_07 and B1-2019_0

A numerical simulation study of the hydrodynamic effects caused by morphological changes in the Guadalquivir River Estuary

This study presents an analysis of the impacts of the changes in bottom depth along the Guadalquivir Estuary on tidal dynamics. A realistic non-linear 1D numerical model, incorporating changes in both breadth and bottom depth, was employed to investigate the involved effects. The findings reveal a significant amplification of the M2 tidal wave towards the upper region of the Estuary, resulting from the gradual deepening caused by multiple dredging operations. The Estuary exhibits a pronounced tendency towards resonance, which is further enhanced by its deepening, resulting in reduced bottom friction and a smaller decrease in tidal wave amplitude as it propagates through the Estuary. The alterations in depth, particularly in breadth, along the Estuary play a crucial role in determining the magnitude of the resonant response of the M2 tidal wave.12 página

Transgenic Mouse Models of Alzheimer’s Disease: An Integrative Analysis

Alzheimer’s disease (AD) constitutes the most prominent form of dementia among elderly individuals worldwide. Disease modeling using murine transgenic mice was first initiated thanks to the discovery of heritable mutations in amyloid precursor protein (APP) and presenilins (PS) genes. However, due to the repeated failure of translational applications from animal models to human patients, along with the recent advances in genetic susceptibility and our current understanding on disease biology, these models have evolved over time in an attempt to better reproduce the complexity of this devastating disease and improve their applicability. In this review, we provide a comprehensive overview about the major pathological elements of human AD (plaques, tauopathy, synaptic damage, neuronal death, neuroinflammation and glial dysfunction), discussing the knowledge that available mouse models have provided about the mechanisms underlying human disease. Moreover, we highlight the pros and cons of current models, and the revolution offered by the concomitant use of transgenic mice and omics technologies that may lead to a more rapid improvement of the present modeling batterThis research was funded by INSTITUTO DE SALUD CARLOS III (ISCiii) of Spain, cofinanced by FEDER funds from European Union, through grants PI21/00915 (to AG) and PI21/00914 (to JV); by JUNTA DE ANDALUCIA CONSEJERÍA DE ECONOMÍA Y CONOCIMIENTO through grants UMA18-FEDERJA-211 (to AG), UMA20-FEDERJA-104 (to IMG), P18-RT-2233 (to AG) and US-1262734 (to JV) co-financed by Programa Operativo FEDER 2014–2020 and CONSEJERIA DE SALUD grant PI-0276-2018 (to JAGL); by SPANISH MINISTER OF SCIENCE AND INNOVATION grant PID2019-108911RA-100 (to DBV), BEATRIZ GALINDO PROGRAM BAGAL18/00052 (to DBV), Alzheimer Association AARG-22-928219 (to DBV), grant PID2019-107090RA-100 (to IMG) and RAMON Y CAJAL PROGRAM RYC-2017-21879 (to IMG); and by MALAGA UNIVERSITY grant B1-2019_07 (to ESM), grant B1-2020_04 (to JAGL), grant B1-2019_06 (to IMG) and NASARD grant 27565 2018 (to IMG). M.M.-O. held a predoctoral contract from Malaga University, J.J.F.-V. held a postdoctoral contract from Malaga University, and E.S.-M. a postdoctoral contract (DOC_00251) from Junta de Andalucia. Partial funding for open access charge: Universidad de Málaga

Plaque-Associated Oligomeric Amyloid-Beta Drives Early Synaptotoxicity in APP/PS1 Mice Hippocampus: Ultrastructural Pathology Analysis

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by initial memory impairments that progress to dementia. In this sense, synaptic dysfunction and loss have been established as the pathological features that best correlate with the typical early cognitive decline in this disease. At the histopathological level, post mortem AD brains typically exhibit intraneuronal neurofibrillary tangles (NFTs) along with the accumulation of amyloid-beta (Abeta) peptides in the form of extracellular deposits. Specifically, the oligomeric soluble forms of Abeta are considered the most synaptotoxic species. In addition, neuritic plaques are Abeta deposits surrounded by activated microglia and astroglia cells together with abnormal swellings of neuronal processes named dystrophic neurites. These periplaque aberrant neurites are mostly presynaptic elements and represent the first pathological indicator of synaptic dysfunction. In terms of losing synaptic proteins, the hippocampus is one of the brain regions most affected in AD patients. In this work, we report an early decline in spatial memory, along with hippocampal synaptic changes, in an amyloidogenic APP/PS1 transgenic model. Quantitative electron microscopy revealed a spatial synaptotoxic pattern around neuritic plaques with significant loss of periplaque synaptic terminals, showing rising synapse loss close to the border, especially in larger plaques. Moreover, dystrophic presynapses were filled with autophagic vesicles in detriment of the presynaptic vesicular density, probably interfering with synaptic function at very early synaptopathological disease stages. Electron immunogold labeling showed that the periphery of amyloid plaques, and the associated dystrophic neurites, was enriched in Abeta oligomers supporting an extracellular location of the synaptotoxins. Finally, the incubation of primary neurons with soluble fractions derived from 6-month-old APP/PS1 hippocampus induced significant loss of synaptic proteins, but not neuronal death. Indeed, this preclinical transgenic model could serve to investigate therapies targeted at initial stages of synaptic dysfunction relevant to the prodromal and early AD.This study was supported by the Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by the FEDER funds from European Union, through grants PI18/01557 (to AG) and PI18/01556 (to JV); by the Junta de Andalucia Consejería de Economía y Conocimiento through grants UMA18-FEDERJA-211 (to AG), P18-RT-2233 (to AG), and US-1262734 (to JV) co-financed by Programa Operativo FEDER 2014–2020; by the Spanish Minister of Science and Innovation grant PID2019-108911RA-100 (to DB-V), Beatriz Galindo program BAGAL18/00052 (to DB-V) grant PID2019-107090RA-I00 (to IM-G), and Ramon y Cajal Program RYC-2017-21879 (to IM-G); and by the Malaga University grants B1-2019_07 (to ES-M) and B1-2019_06 (to IM-G). MM-O held a predoctoral contract from Malaga University and ES-M a postdoctoral contract (DOC_00251) from Junta de Andalucia

Monocyte-derived cells invade brain parenchyma and amyloid plaques in human Alzheimer’s disease hippocampus

© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Microglia are brain-resident myeloid cells and play a major role in the innate immune responses of the CNS and the pathogenesis of Alzheimer's disease (AD). However, the contribution of nonparenchymal or brain-infiltrated myeloid cells to disease progression remains to be demonstrated. Here, we show that monocyte-derived cells (MDC) invade brain parenchyma in advanced stages of AD continuum using transcriptional analysis and immunohistochemical characterization in post-mortem human hippocampus. Our findings demonstrated that a high proportion (60%) of demented Braak V–VI individuals was associated with up-regulation of genes rarely expressed by microglial cells and abundant in monocytes, among which stands the membrane-bound scavenger receptor for haptoglobin/hemoglobin complexes or Cd163. These Cd163-positive MDC invaded the hippocampal parenchyma, acquired a microglial-like morphology, and were located in close proximity to blood vessels. Moreover, and most interesting, these invading monocytes infiltrated the nearby amyloid plaques contributing to plaque-associated myeloid cell heterogeneity. However, in aged-matched control individuals with hippocampal amyloid pathology, no signs of MDC brain infiltration or plaque invasion were found. The previously reported microglial degeneration/dysfunction in AD hippocampus could be a key pathological factor inducing MDC recruitment. Our data suggest a clear association between MDC infiltration and endothelial activation which in turn may contribute to damage of the blood brain barrier integrity. The recruitment of monocytes could be a consequence rather than the cause of the severity of the disease. Whether monocyte infiltration is beneficial or detrimental to AD pathology remains to be fully elucidated. These findings open the opportunity to design targeted therapies, not only for microglia but also for the peripheral immune cell population to modulate amyloid pathology and provide a better understanding of the immunological mechanisms underlying the progression of AD.This study was supported by Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union, through grants PI18/01556 and PI21/00914 (to JV) and PI18/01557 and PI21/00915 (to AG); by Junta de Andalucia Consejería de Economía y Conocimiento through grants US-1262734 and P20-00843 (to JV), UMA18-FEDERJA-211 (to AG) and PI18-RT-2233 (to AG) co-financed by Programa Operativo FEDER 2014-2020; by Spanish Minister of Science and Innovation grant PID2019-108911RA-100 (to DBV), Beatriz Galindo Program BAGAL18/00052 (to DBV), grant PID2019-107090RA-I00 (to IMG) and Ramon y Cajal Program RYC-2017-21879 (to IMG); and by Malaga University grant B-2019_06 (to ESM).Peer reviewe

Heterogeneidad regional de la respuesta microglial asociada a la patología amiloide en la enfermedad de Alzheimer.

El objetivo principal de esta Tesis Doctoral ha sido caracterizar, a nivel celular y molecular, los fenotipos morfológicos y estados funcionales/disfuncionales de las células mieloides (microglía y monocitos infiltrados) en la corteza frontal e hipocampo humano post mortem de individuos dentro del continuo Alzheimer. Además, se han comparado estos perfiles mieloides en un modelo amiloidogénico murino de disfunción microglial (APP/Trem2KO). Los resultados más relevantes han sido los siguientes: 1) existe una notable heterogeneidad regional en la respuesta microglial en el cerebro humano, con una fuerte activación microglial en la corteza frontal, similar a la que existes en los modelos animales amiloidogénicos, mientras que en el hipocampo de los mismos individuos la activación microglial está muy limitada y presenta un fenotipo degenerativo, similar a lo que ocurre en el modelo APP/Trem2KO; 2) las células microgliales asociadas a las placas amiloides expresan los marcadores Iba1, CD32, CD74, Tmem119, CD68, Trem2, Gal3 y CD45high, llegando a expresar un subconjunto de estas células también el marcador de senescencia ferritina; y 3) en etapas avanzadas de la patología células periféricas derivadas de monocitos (CDM) invaden el parénquima cerebral. Estas células CD163+ infiltradas adquieren una apariencia microglial, se concentran cerca de vasos sanguíneos e invaden las placas amiloides, contribuyendo así a la heterogeneidad de las células mieloides asociadas a las placas. Por el contrario, en el parénquima de individuos asintomáticos con placas amiloides y reactividad microglial no se ha observado la presencia de CDM. El reclutamiento de estas células podría ser una consecuencia más que una causa de la gravedad de la AD, siendo aún necesario comprender mejor el impacto que esta población celular puede ejercer en la patología Alzheimer. Estos hallazgos presentan una nueva oportunidad para proponer nuevas dianas terapéuticas dirigidas no solo a la microglía, sino también a otras poblaciones mieloides periféricas, con el objetivo de crear nuevas estrategias farmacológicas encaminadas a modular la patología amiloide y modificar el curso de la enfermedad. Los modelos animales con disfunción microglial mimetizan mejor el contexto patológico humano de regiones como el hipocampo, siendo de mayor valor predictivo para los estudios preclínicos y su traslación a la clínica humana.La enfermedad de Alzheimer (AD), principal causa de demencia y discapacidad, es la patología neurodegenerativa más prevalente en los mayores de 65 años y para la cual no existe un tratamiento efectivo. Se trata de una proteinopatía compleja caracterizada por la agregación y acumulación extracelular del péptido β-amiloide en forma de placas amiloides, y a nivel intracelular de la proteína tau hiperfosforilada en forma de ovillos neurofibrilares. Las terapias dirigidas contra ambas lesiones proteicas no han conseguido demostrar todavía beneficio clínico significativo en los pacientes, lo que indica que existen otros mecanismos patogénicos aún sin resolver. En los últimos años, la microglía, células inmunes innatas del cerebro, se ha revelado como factor clave en la AD de tipo esporádico, ya que diversos factores de riesgo genético vinculan la disfunción de estas células gliales con la patogénesis de la enfermedad. La mayor parte de los estudios se han realizado en modelos animales transgénicos para esta enfermedad, sin embargo, la traslación de los resultados de modelos a pacientes no ha tenido éxito, siendo necesario estudiar en detalle la respuesta de estas células gliales en cerebro humano. A día de hoy, aún no se han determinado los diferentes estados funcionales que pueden adoptar la microglía a lo largo del continuo Alzheimer, las diferencias regionales, o la implicación de diferentes subpoblaciones mieloides a la patología humana. Además, tampoco está claro si se produce infiltración de monocitos circulantes en el cerebro de los pacientes, debido a la dificultad de diferenciar ambas poblaciones mieloides a nivel morfológico y molecular. El desarrollo de futuras terapias efectivas dirigidas a modular la microglía requiere conocer todos estos aspectos en muestras humanas