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 | 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: Folch, Jaume | Busquets, Oriol | Ettcheto, Miren | Sánchez-López, Elena | Castro-Torres, Ruben Dario | Verdaguer, Ester | Garcia, Maria Luisa | Olloquequi, Jordi | Casadesús, Gemma | Beas-Zarate, Carlos | Pelegri, Carme | Vilaplana, Jordi | Auladell, Carme | Camins, Antoni
Article Type: Review Article
Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the presence in the brain of extracellular amyloid-β protein (Aβ) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. The N-Methyl-D-aspartate receptors (NMDAR), ionotropic glutamate receptor, are essential for processes like learning and memory. An excessive activation of NMDARs has been associated with neuronal loss. The discovery of extrasynaptic NMDARs provided a rational and physiological explanation between physiological and excitotoxic actions of glutamate. Memantine (MEM), an antagonist of extrasynaptic NMDAR, is currently used for the treatment of AD jointly with acetylcholinesterase inhibitors. It has been demonstrated that MEM preferentially prevents the …excessive continuous extrasynaptic NMDAR disease activation and therefore prevents neuronal cell death induced by excitotoxicity without disrupting physiological synaptic activity. The problem is that MEM has shown no clear positive effects in clinical applications while, in preclinical stages, had very promising results. The data in preclinical studies suggests that MEM has a positive impact on improving AD brain neuropathology, as well as in preventing Aβ production, aggregation, or downstream neurotoxic consequences, in part through the blockade of extrasynaptic NMDAR. Thus, the focus of this review is primarily to discuss the efficacy of MEM in preclinical models of AD, consider possible combinations of this drug with others, and then evaluate possible reasons for its lack of efficacy in clinical trials. Finally, applications in other pathologies are also considered. Show more
Keywords: Alzheimer’s disease, amyloid β-protein, extrasynaptic N-Methyl-D-aspartate receptor, memantine, tau protein
DOI: 10.3233/JAD-170672
Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1223-1240, 2018