Suchergebnisse

Microglial activation has been considered a crucial player in the pathological process of multiple human neurodegenerative diseases. In some of these pathologies, such as Amyotrophic Lateral Sclerosis or Multiple Sclerosis, the immune system and microglial cells (as part of the cerebral immunity) play a central role. In other degenerative processes, such as Alzheimer's disease (AD), the role of microglia is far to be elucidated. In this "mini-review" article, we briefly highlight our recent data comparing the microglial response between amyloidogenic transgenic models, such as APP/PS1 and AD patients. Since the AD pathology could display regional heterogeneity, we focus our work at the hippocampal formation. In APP based models a prominent microglial response is triggered around amyloid-beta (Aβ) plaques. These strongly activated microglial cells could drive the AD pathology and, in consequence, could be implicated in the neurodegenerative process observed in models. On the contrary, the microglial response in human samples is, at least, partial or attenuated. This patent difference could simply reflect the lower and probably slower Aβ production observed in human hippocampal samples, in comparison with models, or could reflect the consequence of a chronic long-standing microglial activation. Beside this differential response, we also observed microglial degeneration in Braak V–VI individuals that, indeed, could compromise their normal role of surveying the brain environment and respond to the damage. This microglial degeneration, particularly relevant at the dentate gyrus, might be mediated by the accumulation of toxic soluble phospho-tau species. The consequences of this probably deficient immunological protection, observed in AD patients, are unknown. ; This work was supported by Fondo de Investigación Sanitaria (FIS) from the Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union, through grants PI15/00957 (to JV) and PI15/00796 (to AG), CIBERNED (to AG and JV), and by Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucia Proyecto de Excelencia (CTS-2035) (to JV and AG). ; Peer reviewed

Alzheimer's disease is a major neurodegenerative disorder that leads to severe cognitive deficits in the elderly population. Over the past two decades, multiple studies have focused on elucidating the causative factors underlying memory defects in Alzheimer's patients. In this regard, new evidence linking Alzheimer's disease-related pathology and neuronal stem cells suggests that hippocampal neurogenesis impairment is an important factor underlying these cognitive deficits. However, because of conflicting results, the impact of Aβ pathology on neurogenesis/gliogenesis remains unclear. Here, we investigated the effect of Aβ on neuronal and glial proliferation by using an APP/PS1 transgenic model and in vitro assays. Specifically, we showed that neurogenesis is affected early in the APP/PS1 hippocampus, as evidenced by a significant decrease in the proliferative activity due to a reduced number of both radial glia-like neural stem cells (type-1 cells) and intermediate progenitor cells (type-2 cells). Moreover, we demonstrated that soluble Aβ from APP/PS1 mice impairs neuronal cell proliferation using neurosphere cultures. On the other hand, we showed that oligomeric Aβ stimulates microglial proliferation, whereas no effect was observed on astrocytes. These findings indicate that Aβ has a differential effect on hippocampal proliferative cells by inhibiting neuronal proliferation and triggering the formation of microglial cells. ; This study was supported by Institute of Health Carlos III (ISCiii, Spain) through grants PI12/01431, PI15/00796 (to AG) and PI12/01439, PI15/00957 (to JV) that were co-financed by FEDER funds from European Union, by Junta de Andalucia Proyecto de Excelencia CTS-2035 (to JV and AG), Alzheimer's Association NIRG-15-363477 (to DBV) and The Larry Hillblom Foundation #2013-A-016-FEL (to DBV). ; Peer reviewed

Reactive astrocytes and dystrophic neurites, most aberrant presynaptic elements, are found surrounding amyloid‐β plaques in Alzheimer's disease (AD). We have previously shown that reactive astrocytes enwrap, phagocytose, and degrade dystrophic synapses in the hippocampus of APP mice and AD patients, but affecting less than 7% of dystrophic neurites, suggesting reduced phagocytic capacity of astrocytes in AD. Here, we aimed to gain insight into the underlying mechanisms by analyzing the capacity of primary astrocyte cultures to phagocytose and degrade isolated synapses (synaptoneurosomes, SNs) from APP (containing dystrophic synapses and amyloid‐β peptides), Tau (containing AT8‐ and AT100‐positive phosphorylated Tau) and WT (controls) mice. We found highly reduced phagocytic and degradative capacity of SNs‐APP, but not AT8/AT100‐positive SNs‐Tau, as compared with SNs‐WT. The reduced astrocyte phagocytic capacity was verified in hippocampus from 12‐month‐old APP mice, since only 1.60 ± 3.81% of peri‐plaque astrocytes presented phagocytic structures. This low phagocytic capacity did not depend on microglia‐mediated astrocyte reactivity, because removal of microglia from the primary astrocyte cultures abrogated the expression of microglia‐dependent genes in astrocytes, but did not affect the phagocytic impairment induced by oligomeric amyloid‐β alone. Taken together, our data suggest that amyloid‐β, but not hyperphosphorylated Tau, directly impairs the capacity of astrocytes to clear the pathological accumulation of oligomeric amyloid‐β, as well as of peri‐plaque dystrophic synapses containing amyloid‐β, perhaps by reducing the expression of phagocytosis receptors such as Mertk and Megf10, thus increasing neuronal damage in AD. Therefore, the potentiation or recovery of astrocytic phagocytosis may be a novel therapeutic avenue in AD. ; Research funding: Centro de Invesitgacion Biomedica en Red Enfermedades Neurodegenetativas (CIBERNED). Grant Numbers: CB06/05/0094, CB06/05/1116; Instituto de Salud Carlos III co‐financed by FEDER funds from European Union. Grant Numbers: PI18/01556, PI18/01557; Junta de Andalucia Consejería de Economía y Conocimiento co‐financed by Programa Operativo FEDER 2014‐2020. Grant Numbers: PY18‐RT‐2233, UMA18‐FEDERJA‐211, US‐1262734; La Marató‐TV3 Foundation. Grant Numbers: 20141430, 20141431, 20141432.

Neuronal loss is the best neuropathological substrate that correlates with cortical atrophy and dementia in Alzheimer's disease (AD). Defective GABAergic neuronal functions may lead to cortical network hyperactivity and aberrant neuronal oscillations and in consequence, generate a detrimental alteration in memory processes. In this study, using immunohistochemical and stereological approaches, we report that the two major and non‐overlapping groups of inhibitory interneurons (SOM‐cells and PV‐cells) displayed distinct vulnerability in the perirhinal cortex of APP/PS1 mice and AD patients. SOM‐positive neurons were notably sensitive and exhibited a dramatic decrease in the perirhinal cortex of 6‐month‐old transgenic mice (57% and 61% in areas 36 and 35, respectively) and, most importantly, in AD patients (91% in Braak V–VI cases). In addition, this interneuron degenerative process seems to occur in parallel, and closely related, with the progression of the amyloid pathology. However, the population expressing PV was unaffected in APP/PS1 mice while in AD brains suffered a pronounced and significant loss (69%). As a key component of cortico‐hippocampal networks, the perirhinal cortex plays an important role in memory processes, especially in familiarity‐based memory recognition. Therefore, disrupted functional connectivity of this cortical region, as a result of the early SOM and PV neurodegeneration, might contribute to the altered brain rhythms and cognitive failures observed in the initial clinical phase of AD patients. Finally, these findings highlight the failure of amyloidogenic AD models to fully recapitulate the selective neuronal degeneration occurring in humans. ; This study was supported by Instituto de Salud Carlos III (ISCiii) of Spain, co‐financed by FEDER funds from European Union, through grants PI18/01557 (to AG) and PI18/01556 (to JV), and CIBERNED (to AG and JV), by Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucia Proyecto de Excelencia (CTS‐2035) (to JV and AG); by Malaga University grant PPIT.UMA.B1.2017/26 (to RSV). CND and JJFV were supported by FPI (Junta Andalucía) and FPU (Spanish Ministry of Science, Innovation and Universities) PhD fellowships, respectively. MMO held a Garantia Juvenil (Junta Andalucia) contract. RSV and JAGL held a postdoctoral contract from the University of Malaga, and AGA from CIBERNED. ; Peer reviewed

In Alzheimer's disease (AD), and other tauopathies, microtubule destabilization compromises axonal and synaptic integrity contributing to neurodegeneration. These diseases are characterized by the intracellular accumulation of hyperphosphorylated tau leading to neurofibrillary pathology. AD brains also accumulate amyloid-beta (Aβ) deposits. However, the effect of microtubule stabilizing agents on Aβ pathology has not been assessed so far. Here we have evaluated the impact of the brain-penetrant microtubule-stabilizing agent Epothilone D (EpoD) in an amyloidogenic model of AD. Three-month-old APP/PS1 mice, before the pathology onset, were weekly injected with EpoD for 3 months. Treated mice showed significant decrease in the phospho-tau levels and, more interesting, in the intracellular and extracellular hippocampal Aβ accumulation, including the soluble oligomeric forms. Moreover, a significant cognitive improvement and amelioration of the synaptic and neuritic pathology was found. Remarkably, EpoD exerted a neuroprotective effect on SOM-interneurons, a highly AD-vulnerable GABAergic subpopulation. Therefore, our results suggested that EpoD improved microtubule dynamics and axonal transport in an AD-like context, reducing tau and Aβ levels and promoting neuronal and cognitive protection. These results underline the existence of a crosstalk between cytoskeleton pathology and the two major AD protein lesions. Therefore, microtubule stabilizers could be considered therapeutic agents to slow the progression of both tau and Aβ pathology. ; This study was supported by Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union, through grants PI15/00796 and PI18/01557 (both to AG), PI15/00957 and PI18/01556 (both to JV), and CIBERNED (CB06/05/1116 to AG and CB06/05/0094 to JV); by Malaga University grant PPIT.UMA.B1.2017/26 (to RSV). JJFV and CMC were supported by FPU PhD fellowships (Spanish Ministry of Science, Innovation and Universities). RSV held a postdoctoral contract from Malaga University. IMG is recipient of a senior postdoctoral contract from Ramon y Cajal Program (Spain Government).

Alzheimer's disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (Aβ) peptide, fibrillary tangles of intraneuronal tau and microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimer's disease) mice and found specifically expressed in microglia associated with Aβ plaques. Single-nucleotide polymorphisms in the LGALS3 gene, which encodes gal3, were associated with an increased risk of AD. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data revealed that gal3 was required to fully activate microglia in response to fibrillar Aβ. Gal3 deletion decreased the Aβ burden in 5xFAD mice and improved cognitive behavior. Interestingly, a single intrahippocampal injection of gal3 along with Aβ monomers in WT mice was sufficient to induce the formation of long-lasting (2 months) insoluble Aβ aggregates, which were absent when gal3 was lacking. High-resolution microscopy (stochastic optical reconstruction microscopy) demonstrated close colocalization of gal3 and TREM2 in microglial processes, and a direct interaction was shown by a fluorescence anisotropy assay involving the gal3 carbohydrate recognition domain. Furthermore, gal3 was shown to stimulate TREM2–DAP12 signaling in a reporter cell line. Overall, our data support the view that gal3 inhibition may be a potential pharmacological approach to counteract AD. ; This work was supported by Grants from the Swedish Research Council, and the Strong Research Environment MultiPark (Multidisciplinary Research in Parkinson's and Alzheimer's Disease at Lund University), Bagadilico (Linné consortium sponsored by the Swedish Research Council), the Swedish Alzheimer's Foundation, Swedish Brain Foundation, A.E. Berger Foundation, Gyllenstiernska Krapperup Foundation, the Royal Physiographic Society, Crafoord Foundation, Olle Engkvist Byggmästare Foundation, Wiberg Foundation, G&J Kock Foundation, Stohnes Foundation, Swedish Dementia Association and the Medical Faculty at Lund University. This work was supported by Grant SAF2015-64171R (Spanish MINECO/FEDER, UE), by Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union through grants PI15/00796 and PI18/01557 (to AG), PI15/00957 and PI18/01556 (to JV), and CIBERNED (to AG and JV), by Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucia Proyecto de Excelencia (CTS-2035) (to JV and AG), and by Malaga University grant PPIT.UMA.B1.2017/26 (to RSV). AV and GCB received funding from the Innovative Medicines Initiative 2 Joint Undertaking under Grant agreement no. 115976 (PHAGO). CIBERNED "Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid (Spain)". HL and AF were supported by the Swedish Research Council, the Swedish Brain Foundation, the Alzheimer Foundation and the Åhlén Foundation. UJN was supported by Grants from the Knut and Alice Wallenberg Foundation (KAW 2013.0022) and the Swedish Research Council (Grant no. 621-2012-2978). ; Peer reviewed

Genetic Alzheimer's disease (AD) risk factors associate with reduced defensive amyloid β plaque-associated microglia (AβAM), but the contribution of modifiable AD risk factors to microglial dysfunction is unknown. In AD mouse models, we observe concomitant activation of the hypoxia-inducible factor 1 (HIF1) pathway and transcription of mitochondrial-related genes in AβAM, and elongation of mitochondria, a cellular response to maintain aerobic respiration under low nutrient and oxygen conditions. Overactivation of HIF1 induces microglial quiescence in cellulo, with lower mitochondrial respiration and proliferation. In vivo, overstabilization of HIF1, either genetically or by exposure to systemic hypoxia, reduces AβAM clustering and proliferation and increases Aβ neuropathology. In the human AD hippocampus, upregulation of HIF1α and HIF1 target genes correlates with reduced Aβ plaque microglial coverage and an increase of Aβ plaque-associated neuropathology. Thus, hypoxia (a modifiable AD risk factor) hijacks microglial mitochondrial metabolism and converges with genetic susceptibility to cause AD microglial dysfunction. ; R.M.-D. was the recipient of a Sara Borrell fellowship from Instituto de Salud Carlos III (ISCIII) (CD09/0007). N.L.-U., C.O.-d.S.L., C.R.-M. and M.I.A.-V. were the recipients of FPU fellowships from Spanish Ministry of Education, Culture and Sport (FPU14/02115, AP2010‐1598, FPU16/02050 and FPU15/02898, respectively). A.H.-G. was the recipient of an FPI fellowship from the Spanish Ministry of Education, Culture and Sport (BES-2010-033886). This work was supported by grants from the Spanish MINEICO, ISCIII and FEDER (European Union) (SAF2012‐33816, SAF2015‐64111‐R, SAF2017-90794-REDT and PIE13/0004 to A.P.); by the Regional Government of Andalusia co-funded by CEC and FEDER funds (European Union) ('Proyectos de Excelencia'; P12‐CTS‐2138 and P12‐CTS‐2232 to A.P.); by the 'Ayuda de Biomedicina 2018', Fundación Domingo Martínez (to A.P.) ; by the ISCIII of Spain, co-financed by FEDER funds (European Union) through grants PI18/01556 (to J.V.) and PI18/01557 (to A. Gutierrez); by Junta de Andalucía, co-financed by FEDER funds (grants UMA18-FEDERJA-211 (to A. Gutierrez) and US‐1262734 (to J.V.)); and by Spanish MINEICO (BFU2016-76872-R and BES-2011-047721 to E.B.). ; No

The human Alzheimer's disease (AD) brain accumulates angiogenic markers but paradoxically, the cerebral microvasculature is reduced around Aß plaques. Here we demonstrate that angiogenesis is started near Aß plaques in both AD mouse models and human AD samples. However, endothelial cells express the molecular signature of non-productive angiogenesis (NPA) and accumulate, around Aß plaques, a tip cell marker and IB4 reactive vascular anomalies with reduced NOTCH activity. Notably, NPA induction by endothelial loss of presenilin, whose mutations cause familial AD and which activity has been shown to decrease with age, produced a similar vascular phenotype in the absence of Aß pathology. We also show that Aß plaque-associated NPA locally disassembles blood vessels, leaving behind vascular scars, and that microglial phagocytosis contributes to the local loss of endothelial cells. These results define the role of NPA and microglia in local blood vessel disassembly and highlight the vascular component of presenilin loss of function in AD. ; A.E.R.-N. was the recipient of a JdlC-F fellowship from the Spanish Ministry of Economy, Industry, and Competitiveness (MINEICO) (FJCI-2015-23708), M.I.A.-V., N.L.-U., and C.O.-d.S.L. were the recipient of an FPU fellowship from Spanish Ministry of Education, Culture, and Sport (respectively, FPU15/02898, FPU14-02115, and AP2010‐1598), and R.M.-D. was the recipient of a "Sara Borrell" fellowship from ISCIII (CD09/0007). Work was supported by grants to A.P. by the Spanish MINEICO, ISCIII, and FEDER (SAF2012‐33816, SAF2015‐64111‐R, RTI2018-096629-B-100, SAF2017-90794-REDT, and PIE13/0004), by the regional Government of Andalusia ("Proyectos de Excelencia", P12‐CTS‐2138 and P12‐CTS‐2232) co-funded by CEC and FEDER funds, and by the "Ayuda de Biomedicina 2018", Fundación Domingo Martínez; J.Vitorica: Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union (PI18/01556) by La Marató-TV3 Foundation grant 20141431; by CIBERNED (CB06/05/0094); and by Junta de Andalucia Consejería de Economía y Conocimiento through grant US-1262734; A.G.: Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union, through grant PI18/01557; and by Junta de Andalucia Consejería de Economía y Conocimiento through grants UMA18-FEDERJA-211 and P18-RT-2233 co-financed by Programa Operativo FEDER 2014-2020. ; Peer reviewed