Early neuropathology of somatostatin/NPY GABAergic cells in the hippocampus of a PS1×APP transgenic model of Alzheimer's disease

Ramos, Blanca Patricia Lazalde; Baglietto‐Vargas, David; Río, Juan Carlos del; Moreno-González, Inés; Santa-María, Consuelo; Jiménez, Sebastián; Caballero, Cristina; López‐Téllez, Juan F.; Khan, Zafar U.; Ruano, Diego; Gutiérrez, Antonia; Vitórica, Javier

doi:10.1016/j.neurobiolaging.2005.09.022

Cited by 186 publications

(233 citation statements)

References 53 publications

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“…These bigenic mice were obtained (see Blanchard et al, 2003) by crossing homozygous PS1 mice (expressing human mutant PS1[M146L] under HMGCoA reductase promoter) to hemizygous APP751SL mice (expressing human mutant APP751 carrying the Swedish [KM670/671NL] and London [V717I] mutations under the control of the Thy1 promoter). We have previously characterized this APP/PS1 transgenic model (Baglietto‐Vargas et al, 2010; Jimenez et al, 2008; Ramos et al, 2006; Sanchez‐Varo et al, 2012; Torres et al, 2012; Trujillo‐Estrada et al, 2014). Age‐matched non‐transgenic mice (WT) of the same genetic background (C57BL:6) were used as controls.…”

Section: Methodsmentioning

confidence: 99%

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

Gómez-Arboledas

Dávila

Sánchez-Mejías

et al. 2017

Glia

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163

126

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Reactive astrogliosis, a complex process characterized by cell hypertrophy and upregulation of components of intermediate filaments, is a common feature in brains of Alzheimer's patients. Reactive astrocytes are found in close association with neuritic plaques; however, the precise role of these glial cells in disease pathogenesis is unknown. In this study, using immunohistochemical techniques and light and electron microscopy, we report that plaque‐associated reactive astrocytes enwrap, engulf and may digest presynaptic dystrophies in the hippocampus of amyloid precursor protein/presenilin‐1 (APP/PS1) mice. Microglia, the brain phagocytic population, was apparently not engaged in this clearance. Phagocytic reactive astrocytes were present in 35% and 67% of amyloid plaques at 6 and 12 months of age, respectively. The proportion of engulfed dystrophic neurites was low, around 7% of total dystrophies around plaques at both ages. This fact, along with the accumulation of dystrophic neurites during disease course, suggests that the efficiency of the astrocyte phagocytic process might be limited or impaired. Reactive astrocytes surrounding and engulfing dystrophic neurites were also detected in the hippocampus of Alzheimer's patients by confocal and ultrastructural analysis. We posit that the phagocytic activity of reactive astrocytes might contribute to clear dysfunctional synapses or synaptic debris, thereby restoring impaired neural circuits and reducing the inflammatory impact of damaged neuronal parts and/or limiting the amyloid pathology. Therefore, potentiation of the phagocytic properties of reactive astrocytes may represent a potential therapy in Alzheimer's disease.

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Section: Methodsmentioning

confidence: 99%

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

Gómez-Arboledas

Dávila

Sánchez-Mejías

et al. 2017

Glia

Self Cite

163

126

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“…It was not our intention to determine the total immunostained cell number in the whole mouse hippocampus. We are aware that, if this was the aim, Cavalieri point count in combination with three-dimensional optical dissector methods would be more appropriate (Ramos et al, 2006). All analysis was performed by a scientist blinded to the genotype status of the animal.…”

Section: Histological Analysismentioning

confidence: 99%

“…The focus of analysis was laid on areas with considerable presence of SOM-positive cells. This subpopulation of GABAergic interneurons has a limited distribution in CA1 hippocampal region, in which highest density is found in stratum oriens, but none in stratum radiatum and very few in stratum lacunosum-moleculare (Vela et al, 2003;Ramos et al, 2006). Therefore, we included only stratum oriens and stratum lacunosum-moleculare and the dentate gyrus for comparison into analysis (Fig.…”

Section: Quantification Of Somatostatin-positive Cells In Tg2576 Micementioning

confidence: 99%

Reduced Spine Density in Specific Regions of CA1 Pyramidal Neurons in Two Transgenic Mouse Models of Alzheimer's Disease

Pérez-Cruz¹,

Nolte²,

Gaalen³

et al. 2011

J. Neurosci.

158

120

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One major hallmark of Alzheimer's disease (AD) is the massive loss of synapses that occurs at an early clinical stage of the disease. In this study, we characterize alterations in spine density and the expression of synapse-associated immediate early gene Arc (activity-regulated cytoskeleton-associated protein) in the hippocampal CA1 regions of two different amyloid precursor protein (APP) transgenic mouse lines before plaque development and their connection to performance in hippocampus-dependent memory tests. The density of mushroom-type spines was reduced by 34% in the basal dendrites proximal to the soma of CA1 pyramidal neurons in 5.5-month-old Tg2576 mice, carrying the Swedish mutation, compared with wild-type littermates. A similar reduction of 42% was confirmed in the same region of 8-month-old APP/Lo mice, carrying the London mutation. In this strain, the reduction extended to the distal dendritic spines (28%), although no differences were found in apical dendrites in either transgenic mouse line. Both transgenic mice lines presented a significant increase in Arc protein expression in CA1 compared with controls, suggesting rather an overactivity and increased spine turnover that was supported by a significant decrease in number of somatostatin-immunopositive inhibitory interneurons in the stratum oriens of CA1. Behaviorally, the transgenic mice showed decrease freezing in the fear contextual conditioning test and impairment in spatial memory assessed by Morris water maze test. These data indicate that cognitive impairment in APP transgenic mice is correlated with impairment of synaptic connectivity in hippocampal CA1, probably attributable to loss of inhibitory interneurons and subsequent hyperactivity.

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“…In the hippocampus, a substantial early loss of SRIF-immunopositive neurons and SRIF mRNA was detected in a transgenic mouse model of AD, in the absence of changes in other neuronal markers of GABAergic, glutamatergic and cholinergic systems or in the principal cell number (Ramos et al, 2006). Furthermore, a linear correlation between SRIF deficiency and A content was observed.…”

Section: Somatostatin and The Modulation Of Adenylyl Cyclase Activitymentioning

confidence: 93%

“…Furthermore, a linear correlation between SRIF deficiency and A content was observed. In view of these Page 7 of 31 A c c e p t e d M a n u s c r i p t 7 findings, SRIF could constitute an important biomarker to assess the efficacy of potential early AD treatments (Ramos et al, 2006).…”

Section: Somatostatin and The Modulation Of Adenylyl Cyclase Activitymentioning

confidence: 99%

Somatostatin and Alzheimer's disease

Burgos‐Ramos

Hervás-Aguilar

Aguado-Llera

et al. 2008

Molecular and Cellular Endocrinology

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Early neuropathology of somatostatin/NPY GABAergic cells in the hippocampus of a PS1×APP transgenic model of Alzheimer's disease

Cited by 186 publications

References 53 publications

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

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

Reduced Spine Density in Specific Regions of CA1 Pyramidal Neurons in Two Transgenic Mouse Models of Alzheimer's Disease

Somatostatin and Alzheimer's disease

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