Extracellular Amyloid-β and Cytotoxic Glial Activation Induce Significant Entorhinal Neuron Loss in Young PS1M146L/APP751SL Mice

Moreno-González, Inés; Baglietto‐Vargas, David; Sánchez-Varo, Raquel; Jiménez, Sebastián; Trujillo‐Estrada, Laura; Sánchez-Mejías, Elisabeth; Río, Juan Carlos del; Torres, M.; Romero-Acebal, Manuel; Ruano, Diego; Vizuete, Marisa; Vitórica, Javier; Gutiérrez, Antonia

doi:10.3233/jad-2009-1192

Cited by 41 publications

(84 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The most relevant discrepancy is the scarce or delayed neuronal loss in AD models concomitant with the accumulation of extracellular/intracellular amyloid-β (Aβ). We have recently reported a significant entorhinal principal cell loss in 6 month-old PS1 M146L /AβPP751 SL mice that was induced by extracellular, not intracellular, Aβ accumulation [3]. This early principal cell neurodegeneration in the entorhinal cortex was previous to that seen in hippocampus (18 months) as described in AD patients.…”

Section: Introductionmentioning

confidence: 82%

“…This early principal cell neurodegeneration in the entorhinal cortex was previous to that seen in hippocampus (18 months) as described in AD patients. Moreover, both brain areas in this transgenic mice display a prominent early reduction of SOM/NPY interneurons of GABA system [3,4] as occurs in AD brains [5][6][7][8][9][10][11][12]. Therefore, this PS1/AβPP mouse could mimic the initial stages of the pathology in humans and could be of great interest to analyze the age-dependent vulnerability of different neuronal subpopulations to this disease.…”

Section: Introductionmentioning

confidence: 99%

“…Serial sections from PS1/AβPP, PS1, and WT mice were assayed simultaneously for light microscopy immunohistochemistry as previously reported [3,4]. Briefly, free-floating sections were first pretreated with 3% H 2 O 2 /3% methanol in PBS and with avidinbiotin Blocking Kit (Vector Labs, Burlingame, CA, USA).…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Immunopositive cells for calretinin (CR-positive interneurons and CR-positive Cajal-Retzius population) belonging to the different animal groups (WT, PS1, and PS1/AβPP) and ages (2,4,6, and 12 months) were quantified (n = 5 per genotype and age; 10-12 sections per animal) in the hippocampal formation (CA1 and CA2/3 subfields) according to the optical fractionator method as previously described [3,4]. Reelinpositive Cajal-Retzius cells at the hippocampal fissure were counted at 6 months of age (n = 5 per genotype; 10-12 sections per mouse).…”

Section: Stereological Analysismentioning

confidence: 99%

See 3 more Smart Citations

Calretinin Interneurons are Early Targets of Extracellular Amyloid-β Pathology in PS1/AβPP Alzheimer Mice Hippocampus

Baglietto‐Vargas

Moreno-González

Sánchez-Varo

et al. 2010

JAD

Self Cite

View full text Add to dashboard Cite

Abstract. Specific neuronal networks are preferentially affected in the early stages of Alzheimer's disease (AD). The distinct subpopulations of hippocampal inhibitory GABAergic system have been shown to display differential vulnerability to neurodegeneration in AD. We have previously reported a substantial loss of SOM/NPY interneurons, whereas those expressing parvalbumin were unaltered, in the hippocampus of 6 month-old PS1/AβPP transgenic mice. In the present study, we now investigated the pathological changes of hippocampal calretinin (CR) interneurons in this PS1/AβPP model from 2 to 12 months of age. The total number of CR-immunoreactive inhibitory cells was determined by stereology in CA1 and CA2/3 subfields. Our findings show a substantial decrease (35%-45%) of CR-positive interneurons in both hippocampal subfields of PS1/AβPP mice at very early age (4 months) compared to age-matched control mice. This decrease was accompanied by a reduced CR mRNA content as determined by quantitative RT-PCR. However, the number of another hippocampal CR-positive population (belonging to Cajal-Retzius cells) was not affected. The selective early loss of CR-interneurons was parallel to the appearance of extracellular Aβ deposits, preferentially in CR-axonal fields, and the formation of dystrophic neurites. This specific GABAergic subpopulation plays a crucial role in the generation of synchronous rhythmic activity in hippocampus by controlling other interneurons. Therefore, early alterations of hippocampal inhibitory functionality in AD, caused by select CR-cells neurodegeneration, could result in cognitive impairments seen in initial stages of the disease.

show abstract

Section: Introductionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Section: Immunohistochemistrymentioning

confidence: 99%

Section: Stereological Analysismentioning

confidence: 99%

See 2 more Smart Citations

Calretinin Interneurons are Early Targets of Extracellular Amyloid-β Pathology in PS1/AβPP Alzheimer Mice Hippocampus

Baglietto‐Vargas

Moreno-González

Sánchez-Varo

et al. 2010

JAD

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although IFNγ was not assessed in this study, an age-related increase in hippocampal concentration of this cytokine has been reported (Downer et al, 2009), perhaps released by the infiltrating natural killer (NK) cells which are present in the brain of aged animals (Lyons et al, 2011). Increased iNOS expression in hippocampus has been reported with age (Gavilan 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 et al., 2007) and also in brain tissue obtained from mouse models of Alzheimer's Disease (Moreno-Gonzalez et al, 2009;Yin et al, 2011); in these instances it has been linked with evidence of microglial activation and/or deficits in cognitive function (Yin et al, 2011). Like iNOS mRNA, the present data show that expression of MCP-1 and IP-10 were also increased with age.…”

Section: Discussionmentioning

confidence: 99%

CD200 fusion protein decreases microglial activation in the hippocampus of aged rats

Cox

Carney

Miller

et al. 2012

Brain, Behavior, and Immunity

100

View full text Add to dashboard Cite

Please cite this article as: Fionnuala Cox, F., Carney, D., Miller, A-M., Lynch, M.A., CD200 fusion protein decreases microglial activation in the hippocampus of aged rats, Brain, Behavior, and Immunity (2011), doi: 10.1016/j.bbi. 2011 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractThe glycoprotein, CD200, is primarily expressed on neurons and its cognate receptor CD200R is expressed principally on cells of the myeloid lineage, including microglia. The interaction of CD200 with its receptor plays a significant role in maintaining microglia in a quiescent state and therefore a decrease in CD200 expression in brain is associated with evidence of microglial activation. Conversely, activation of CD200R, for example using a CD200 fusion protein (CD200Fc), should result in a decrease in microglial activation. Here we assessed the effect of delivery of CD200Fc intrahippocampally on microglial activation and on long-term potentiation (LTP) in perforant path-granule cell synapses in young and aged rats. We hypothesized that the age-related changes in microglial activation would be attenuated by CD200Fc resulting in an improved ability of aged rats to sustain LTP. The data indicate that expression of markers of microglial activation including major histocompatibility complex Class II (MHCII) and CD40 mRNA, as well as MHCII immunoreactivity, were increased in hippocampus of aged, compared with young, rats and that these changes were associated with a deficit in LTP; these changes were attenuated in hippocampal tissue prepared from aged rats which received CD200Fc. Microglial activation and a deficit in LTP have also been reported in lipopolysaccharide (LPS)-treated rats and, here, we report that these changes were also attenuated in CD200Fc-treated animals. Thus the negative impact of microglial activation on the ability of aged and LPS-treated rats to sustain LTP is ameliorated when CD200R is activated by CD200Fc.

show abstract

Loss of ferritin‐positive microglia relates to increased iron, RNA oxidation, and dystrophic microglia in the brains of aged male marmosets

Rodríguez-Callejas¹,

Cuervo-Zanatta²,

Rosas‐Arellano³

et al. 2019

American J Primatol

View full text Add to dashboard Cite

number: 308515 Microglia are cells that protect brain tissue from invading agents and toxic substances, first by releasing pro-inflammatory cytokines, and thereafter by clearing tissue by phagocytosis. Microglia express ferritin, a protein with ferroxidase activity capable of storing iron, a metal that accumulates in brain during aging. Increasing evidence suggests that ferritin plays an important role in inflammation. However, it is not known if ferritin/ iron content can be related to the activation state of microglia. To this end, we aimed to delineate the role of ferritin in microglia activation in a non-human primate model. We analyzed brains of male marmosets and observed an increased density of ferritin+ microglia with an activated phenotype in hippocampus and cortex of old marmosets (mean age 11.25 ± 0.70 years) compared to younger subjects. This was accompanied by an increased number of dystrophic microglia in old marmosets. However, in aged subjects (mean age 16.83 ± 2.59 years) the number of ferritin+ microglia was decreased compared to old ones. Meanwhile, the content of iron in brain tissue and cells with oxidized RNA increased during aging in all hippocampal and cortical regions analyzed. Abundant amoeboid microglia were commonly observed surrounding neurons with oxidized RNA. Notably, amoeboid microglia were arginase1+ and IL-10+, indicative of a M2 phenotype. Some of those M2 cells also presented RNA oxidation and a dystrophic phenotype. Therefore, our data suggest that ferritin confers protection to microglia in adult and old marmosets, while in aged subjects the decline in ferritin and the increased amount of iron in brain tissue may be related to the increased number of cells with oxidized RNA, perhaps precluding the onset of neurodegeneration.

show abstract

Extracellular Amyloid-β and Cytotoxic Glial Activation Induce Significant Entorhinal Neuron Loss in Young PS1M146L/APP751SL Mice

Cited by 41 publications

References 39 publications

Calretinin Interneurons are Early Targets of Extracellular Amyloid-β Pathology in PS1/AβPP Alzheimer Mice Hippocampus

Calretinin Interneurons are Early Targets of Extracellular Amyloid-β Pathology in PS1/AβPP Alzheimer Mice Hippocampus

CD200 fusion protein decreases microglial activation in the hippocampus of aged rats

Loss of ferritin‐positive microglia relates to increased iron, RNA oxidation, and dystrophic microglia in the brains of aged male marmosets

Contact Info

Product

Resources

About