Authors: Porquet, David | Griñán-Ferré, Christian | Ferrer, Isidre | Camins, Antoni | Sanfeliu, Coral | del Valle, Jaume | Pallàs, Mercè
Article Type: Research Article
Abstract: The amyloid-β protein precursor/presenilin 1 (AβPP/PS1) mouse model of Alzheimer's disease (AD) has provided robust neuropathological hallmarks of familial AD-like pattern. AD is a neurodegenerative process that causes severe cognitive impairment; it is characterized by the accumulation of amyloid-β (Aβ) and hyperphosphorylated tau forms and by oxidative and inflammatory processes in brain. Currently, efforts are made to understand biochemical pathways because there is no effective therapy for AD. Resveratrol is a polyphenol that induces expression and activation of several neuroprotective pathways involving Sirtuin1 and AMPK. The objective of this work was to assess the effect of oral resveratrol administration on …AβPP/PS1 mice. Long-term resveratrol treatment significantly prevented memory loss as measured by the object recognition test. Moreover, resveratrol reduced the amyloid burden and increased mitochondrial complex IV protein levels in mouse brain. These protective effects of resveratrol were mainly mediated by increased activation of Sirtuin 1 and AMPK pathways in mice. However, an increase has been observed in IL1β and TNF gene expression, indicating that resveratrol promoted changes in inflammatory processes, although no changes were detected in other key actors of the oxidative stress pathway. Taken together, our findings suggest that resveratrol is able to reduce the harmful process that occurs in AβPP/PS1 mouse hippocampus, preventing memory loss. Show more
Keywords: AMPK, inflammation, mitochondria, resveratrol, sirtuin 1
DOI: 10.3233/JAD-140444
Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1209-1220, 2014
Authors: Griñán-Ferré, Christian | Corpas, Rubén | Puigoriol-Illamola, Dolors | Palomera-Ávalos, Verónica | Sanfeliu, Coral | Pallàs, Mercè
Article Type: Review Article
Abstract: Epigenetics is emerging as the missing link among genetic inheritance, environmental influences, and body and brain health status. In the brain, specific changes in nucleic acids or their associated proteins in neurons and glial cells might imprint differential patterns of gene activation that will favor either cognitive enhancement or cognitive loss for more than one generation. Furthermore, derangement of age-related epigenetic signaling is appearing as a significant risk factor for illnesses of aging, including neurodegeneration and Alzheimer’s disease (AD). In addition, better knowledge of epigenetic mechanisms might provide hints and clues in the triggering and progression of AD. Intense research …in experimental models suggests that molecular interventions for modulating epigenetic mechanisms might have therapeutic applications to promote cognitive maintenance through an advanced age. The SAMP8 mouse is a senescence model with AD traits in which the study of epigenetic alterations may unveil epigenetic therapies against the AD. Show more
Keywords: Aging, DNA methylation, epigenetics, histone modification, neurodegeneration
DOI: 10.3233/JAD-170664
Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 943-963, 2018
Authors: Pallas, Merce | Camins, Antoni | Smith, Mark A. | Perry, George | Lee, Hyoung-gon | Casadesus, Gemma
Article Type: Research Article
Abstract: Current mouse models of Alzheimer's disease (AD) are restricted to the expression of AD-related pathology associated with specific mutations present in early-onset familial AD and thus represent <5% of AD cases. To date there are no mouse lines that model late-onset/age-related AD, the feature which accounts for the vast majority of cases. As such, based on current mutation-associated models, the chronology of events that lead to the disease in the aged population is difficult to establish. However, published data show that senescence-accelerated mouse (SAMP8), as a model of aging, display many features that are known to occur early in the …pathogenesis of AD such as increased oxidative stress, amyloid-β alterations, and tau phosphorylation. Therefore, SAMP8 mice may be an excellent model for studying the earliest neurodegenerative changes associated with AD and provide a more encompassing picture of human disease, a syndrome triggered by a combination of age-related events. Here, the neurochemical, neuropathological, and behavioral alterations, characterized in SAMP8 mice are critically reviewed and discussed in relation to the potential use of this mouse model in the study of AD pathogenesis. Show more
Keywords: Aging, Alzheimer's disease, amyloid-β, animal models, cognition, gliosis, neurodegeneration, oxidative stress, SAMP8, tau phosphorylation
DOI: 10.3233/JAD-2008-15408
Citation: Journal of Alzheimer's Disease, vol. 15, no. 4, pp. 615-624, 2008
Authors: Patrick, Sarah | Corrigan, Rachel | Grizzanti, John | Mey, Megan | Blair, Jeff | Pallas, Merce | Camins, Antonio | Lee, Hyoung-gon | Casadesus, Gemma
Article Type: Research Article
Abstract: Administration of the recombinant analog of the pancreatic amyloid amylin, Pramlintide, has shown therapeutic benefits in aging and Alzheimer’s disease (AD) models, both on cognition and amyloid-β (Aβ) pathology. However, the neuroprotective mechanisms underlying the benefits of Pramlintide remain unclear. Given the early and critical role of oxidative stress in AD pathogenesis and the known reactive oxygen species (ROS) modulating function of amyloids, we sought to determine whether Pramlintide’s neuroprotective effects involve regulation of oxidative stress mechanisms. To address this, we treated APP/PS1 transgenic mice with Pramlintide for 3 months, starting at 5.5 months prior to widespread AD pathology onset, …and measured cognition (Morris Water Maze), AD pathology, and oxidative stress-related markers and enzymes in vivo . In vitro , we determined the ability of Pramlintide to modulate H2 O2 -induced oxidative stress levels. Our data show that Pramlintide improved cognitive function, altered amyloid-processing enzymes, reduced plaque burden in the hippocampus, and regulated endogenous antioxidant enzymes (MnSOD and GPx1) and the stress marker HO-1 in a location specific manner. In vitro , Pramlintide treatment in neuronal models reduced H2 O2 -induced endogenous ROS production and lipid peroxidation in a dose-dependent manner. Together, these results indicate that Pramlintide’s benefits on cognitive function and pathology may involve antioxidant-like properties of this compound. Show more
Keywords: Alzheimer’s disease, amylin, metabolism, neuroprotection, oxidative stress, pramlintide
DOI: 10.3233/JAD-180421
Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 157-168, 2019
Authors: Manich, Gemma | Mercader, Clara | del Valle, Jaume | Duran-Vilaregut, Joaquim | Camins, Antoni | Pallàs, Mercè | Vilaplana, Jordi | Pelegrí, Carme
Article Type: Research Article
Abstract: The senescence accelerated mouse-prone 8 (SAMP8) strain of mice is an experimental model of accelerated senescence that has also been proposed as a model of Alzheimer's disease as it shares several features with this dementia. We have recently reported amyloid-β (Aβ) granules in the hippocampus of SAMP8 mice, which contain Aβ42 and Aβ40 peptides and other amyloid-β protein precursor fragments. These granules appear clustered mainly in the stratum radiatum of the CA1 region and increase in number and size with age. Here we performed several studies to examine whether the Aβ granules in the hippocampus of SAMP8 mice contain other …proteins characteristic of neuropathological aggregates, such as tau, MAP2, and α-synuclein. Moreover, we examined whether the Aβ granules in the hippocampus correspond to heparan sulphate proteoglycan (HSPG) positive granules previously described in this animal model. The results showed that Aβ granules correspond to the HSPG granular structures, being syndecan-2, a protein involved in the remodeling of dendritic spines, the type of HSPG found. Tau and MAP2, but not α-synuclein depositions, were also found in Aβ aggregates. Granules do not appear to have an astrocytic origin, since although some Aβ clusters are associated with astrocyte processes, most clusters are not. On the other hand, the presence of tau, MAP2, and NeuN in Aβ granules suggests a neuronal origin. As the components identified in Aβ granules are characteristic of the aggregates present in some neurodegenerative diseases, the SAMP8 model seems to be appropriate for the study of the processes involved in these pathologies. Show more
Keywords: Alzheimer's disease, amyloid-β, hippocampus, HSPG, MAP-2, SAMP8, syndecan, tau
DOI: 10.3233/JAD-2011-101713
Citation: Journal of Alzheimer's Disease, vol. 25, no. 3, pp. 535-546, 2011
Authors: del Valle, Jaume | Bayod, Sergi | Camins, Antoni | Beas-Zárate, Carlos | Velázquez-Zamora, Dulce A. | González-Burgos, Ignacio | Pallàs, Merce
Article Type: Research Article
Abstract: SAMP8 is a strain of mice with accelerated senescence. These mice have recently been the focus of attention as they show several alterations that have also been described in Alzheimer's disease (AD) patients. The number of dendritic spines, spine plasticity, and morphology are basic to memory formation. In AD, the density of dendritic spines is severely decreased. We studied memory alterations using the object recognition test. We measured levels of synaptophysin as a marker of neurotransmission and used Golgi staining to quantify and characterize the number and morphology of dendritic spines in SAMP8 mice and in SAMR1 as control animals. …While there were no memory differences at 3 months of age, the memory of both 6- and 9-month-old SAMP8 mice was impaired in comparison with age-matched SAMR1 mice or young SAMP8 mice. In addition, synaptophysin levels were not altered in young SAMP8 animals, but SAMP8 aged 6 and 9 months had less synaptophysin than SAMR1 controls and also less than 3-month-old SAMP8 mice. Moreover, while spine density remained stable with age in SAMR1 mice, the number of spines started to decrease in SAMP8 animals at 6 months, only to get worse at 9 months. Our results show that from 6 months onwards SAMP8 mice show impaired memory. This age coincides with that at which the levels of synaptophysin and spine density decrease. Thus, we conclude that together with other studies that describe several alterations at similar ages, SAMP8 mice are a very suitable model for studying AD. Show more
Keywords: Alzheimer's disease, dendrites, learning, memory, object recognition test, SAMP8, senescence, synaptophysin
DOI: 10.3233/JAD-2012-120718
Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 233-240, 2012
Authors: del Valle, Jaume | Duran-Vilaregut, Joaquim | Manich, Gemma | Casadesús, Gemma | Smith, Mark A. | Camins, Antoni | Pallàs, Mercè | Pelegrí, Carme | Vilaplana, Jordi
Article Type: Research Article
Abstract: Late-onset Alzheimer's disease (AD) is the most common form of AD appearing after 65 years of age. To date, however, there are no non-genetically manipulated rodent models that develop a similar sporadic onset of AD with age-related amyloid-β (Aβ) deposition. Although the senescence accelerated mouse prone 8 (SAMP8) mice have been proposed as a model of AD, the presence of Aβ deposits remains controversial. In this study, we describe the time course of Aβ deposition in SAMP8 mice as well as in control SAMR1 and ICR-CD1 strains of mice. From as early as 6 months onward, SAMP8 mice show Aβ …deposition in the hippocampus that increase in number and extent with age. These deposits are comprised of by clustered granules that contain Aβ42 , Aβ40 , and other Aβ protein precursor fragments. By marked contrast, control mice show only low numbers of Aβ clusters that do not develop until 15 months of age. The demonstration that SAMP8 mice present with amyloid deposits in their hippocampus makes this animal model a useful tool to understand the mechanisms involved in Aβ deposition in AD. Show more
Keywords: Aβ40, Aβ42, AβPP, aging, Alzheimer's disease, amyloid-β, hippocampus, SAMP8, SAMR1, senescence
DOI: 10.3233/JAD-2010-1321
Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1303-1315, 2010
Authors: Casadesús, Gemma | Gutierrez-Cuesta, Javier | Lee, Hyoung-gon | Jiménez, Andrés | Tajes, Marta | Ortuño-Sahagún, Daniel | Camins, Antoni | Smith, Mark A. | Pallàs, Mercè
Article Type: Research Article
Abstract: Senescence-accelerated mice 8 (SAMP8), a model of aging, display many established pathological features of Alzheimer's disease (AD); however, whether cell cycle alterations exist in these animals remains unknown. Given that these animals present changes such as tau phosphorylation and redox imbalance, both associated with cell cycle alterations, we determined whether changes in cell cycle markers were present in SAMP8 and SAMR1 (control strain) at 3, 6, and 9 months-old brains. As expected, an increase in tau hyperphosphorylation and its associated machinery, i.e., cdk5 and GSK3β, was observed both between strains and also with aging. Particularly, significant differences in cyclin A, …cyclin D1, cyclin E, Cdk2, cyclin B, pR, and E2F1 were found when comparing SAMP8 to SAMR1. More interestingly, a partial correlation with several cell cycle markers described in AD brain is found in SAMP8, indicating that some specific hallmarks of AD are also present in this strain, which has been postulated as an early switch model of the disease. Show more
Keywords: Aging, Alzheimer's disease, cdk5, cell cycle, GSK3β, tau
DOI: 10.3233/JAD-2012-120112
Citation: Journal of Alzheimer's Disease, vol. 30, no. 3, pp. 573-583, 2012
Authors: Ettcheto, Miren | Petrov, Dmitry | Pedrós, Ignacio | Alva, Norma | Carbonell, Teresa | Beas-Zarate, Carlos | Pallas, Merce | Auladell, Carme | Folch, Jaume | Camins, Antoni
Article Type: Research Article
Abstract: Alzheimer’s disease (AD) is currently an incurable aging-related neurodegenerative disorder. Recent studies give support to the hypotheses that AD should be considered as a metabolic disease. The present study aimed to explore the relationship between hippocampal neuropathological amyloid-β (Aβ) plaque formation and obesity at an early presymptomatic disease stage (3 months of age). For this purpose, we used APPswe/PS1dE9 (APP/PS1) transgenic mice, fed with a high-fat diet (HFD) in order to investigate the potential molecular mechanisms involved in both disorders. The results showed that the hippocampus from APP/PS1 mice fed with a HFD had an early significant decrease in Aβ …signaling pathway specifically in the insulin degrading enzyme protein levels, an enzyme involved in (Aβ) metabolism, and α -secretase. These changes were accompanied by a significant increase in the occurrence of plaques in the hippocampus of these mice. Furthermore, APP/PS1 mice showed a significant hippocampal decrease in PGC-1α levels, a cofactor involved in mitochondrial biogenesis. However, HFD does not provoke changes in neither insulin receptors gene expression nor enzymes involved in the signaling pathway. Moreover, there are no changes in any enzymes (kinases) involved in tau phosphorylation, such as CDK5, and neither in brain oxidative stress production. These results suggest that early changes in brains of APP/PS1 mice fed with a HFD are mediated by an increase in Aβ1 ‒ 42 , which induces a decrease in PKA levels and alterations in the p-CREB/ NMDA2B /PGC1-α pathway, favoring early AD neuropathology in mice. Show more
Keywords: Alzheimer’s disease, APPSwe/PS1dE9, hippocampus, insulin receptor, mitochondria, tau
DOI: 10.3233/JAD-160150
Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 233-251, 2016
Authors: Alvarez-López, María Jesús | Castro-Freire, Marco | Cosín-Tomás, Marta | Sanchez-Roige, Sandra | Lalanza, Jaume F. | del Valle, Jaume | Párrizas, Marcelina | Camins, Antonio | Pallás, Merce | Escorihuela, Rosa María | Kaliman, Perla
Article Type: Research Article
Abstract: The senescence-accelerated SAMP8 mouse is considered a useful non-transgenic model for studying aspects of progressive cognitive decline and Alzheimer's disease (AD). Using SAMR1 mice as controls, here we explored the effects of 6 months of voluntary wheel running in 10-month-old female SAMP8 mice. Exercise in SAMP8 mice improved phenotypic features associated with premature aging (i.e., skin color and body tremor) and enhanced vascularization and BDNF gene expression in the hippocampus compared with controls. With the aim of identifying genes involved in brain aging responsive to long-term exercise, we performed whole genome microarray studies in hippocampus from sedentary SAMP8 (P8sed), SAMR1 …(R1sed), and exercised SAMP8 (P8run) mice. The genes differentially expressed in P8sed versus R1sed were considered as putative aging markers (i) and those differentially expressed in P8run versus P8sed were considered as genes modulated by exercise (ii). Genes differentially expressed in both comparisons (i and ii) were considered as putative aging genes responsive to physical exercise. We identified 34 genes which met both criteria. Gene ontology analysis revealed that they are mainly involved in functions related to extracellular matrix maintenance. Selected genes were validated by real-time quantitative PCR assays, i.e., collagen type 1 alpha 1 (col1a1), collagen type 1 alpha 2 (col1a2), fibromodulin (fmod), prostaglandin D(2) synthase (ptgds), and aldehyde dehydrogenase (Aldh1a2). As a whole, our study suggests that exercise training during adulthood may prevent or delay gene expression alterations and processes associated with hippocampal aging in at-risk subjects. Show more
Keywords: Aging, Alzheimer's disease, brain, exercise, gene, long-term, mice, microarrays, SAMP8, voluntary
DOI: 10.3233/JAD-121264
Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 1177-1190, 2013