Past to Future: What Animal Models Have Taught Us About Alzheimer’s Disease
Authors: Martini, Alessandra C. | Forner, Stefania | Trujillo-Estrada, Laura | Baglietto-Vargas, David | LaFerla, Frank M.
Article Type: Review Article
Abstract: Alzheimer’s disease (AD) impairs memory and causes significant cognitive deficits. The disease course is prolonged, with a poor prognosis, and thus exacts an enormous economic and social burden. Over the past two decades, genetically engineered mouse models have proven indispensable for understanding AD pathogenesis, as well as for discovering new therapeutic targets. Here we highlight significant studies from our laboratory that have helped advance the AD field by elucidating key pathogenic processes operative in AD and exploring a variety of aspects of the disease which may yield novel therapeutic strategies for combatting this burdensome disease.
Keywords: 3xTg-AD, amyloid-β, animal models, comorbidities, inflammation, stem cell therapy, synaptic loss, tau
DOI: 10.3233/JAD-179917
Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S365-S378, 2018
Early Neuronal Loss and Axonal/Presynaptic Damage is Associated with Accelerated Amyloid-β Accumulation in AβPP/PS1 Alzheimer's Disease Mice Subiculum
Authors: Trujillo-Estrada, Laura | Dávila, José Carlos | Sánchez-Mejias, Elisabeth | Sánchez-Varo, Raquel | Gomez-Arboledas, Angela | Vizuete, Marisa | Vitorica, Javier | Gutiérrez, Antonia
Article Type: Research Article
Abstract: The progressive cognitive decline leading to dementia in Alzheimer's disease (AD) patients is the consequence of a severe loss of synapses and neurons affecting particular cell subpopulations in selected brain areas, with the subiculum being one of the earliest regions displaying severe atrophy and pathology. The lack of significant neuronal loss in most AD models is, in fact, the major shortcoming for the preclinical evaluation of drugs that could have greater potential in patients to alleviate or prevent this disease. In this study, using immunohistochemical and stereological approaches, we have analyzed the histopathological events in the subiculum of AβPP751SwedLondon/PS1M146L mice, …a transgenic model that displays neuronal vulnerability at early ages in hippocampus and entorhinal cortex. Our results indicate that the subiculum is the earliest affected region in the hippocampus, showing a selective early loss of both principal neurons (28%) and SOM-positive interneurons (69%). In addition, our data demonstrate the existence of an early axonal and synaptic pathology, which may represent the beginning of the synaptic disruption and loss. These neurodegenerative processes occur in parallel, and closely related, with the onset and accelerated progression of the extracellular amyloid-β deposition, thus suggesting plaques as major contributors of neuronal/axonal damage. Data reported here indicate that this AD model displays a selective AD-like neurodegenerative phenotype in highly vulnerable regions, including the subiculum, and therefore can be a very useful model for testing the therapeutic ability of potential compounds to protect neurons and ameliorate disease symptoms. Show more
Keywords: Alzheimer's disease, amyloid-β plaques, axonal damage, hippocampus, neuronal loss, subiculum, transgenic mice
DOI: 10.3233/JAD-140495
Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 521-541, 2014
Calretinin Interneurons are Early Targets of Extracellular Amyloid-β Pathology in PS1/AβPP Alzheimer Mice Hippocampus
Authors: Baglietto-Vargas, David | Moreno-Gonzalez, Ines | Sanchez-Varo, Raquel | Jimenez, Sebastian | Trujillo-Estrada, Laura | Sanchez-Mejias, Elisabeth | Torres, Manuel | Romero-Acebal, Manuel | Ruano, Diego | Vizuete, Marisa | Vitorica, Javier | Gutierrez, Antonia
Article Type: Research Article
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 more
Keywords: Alzheimer's disease, amyloid, hippocampal formation, inhibitory neurons, neurodegeneration, neuropathology, transgenic
DOI: 10.3233/JAD-2010-100066
Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 119-132, 2010
Extracellular Amyloid-β and Cytotoxic Glial Activation Induce Significant Entorhinal Neuron Loss in Young PS1 M146L/APP 751SL Mice
Authors: Moreno-Gonzalez, Ines | Baglietto-Vargas, David | Sanchez-Varo, Raquel | Jimenez, Sebastian | Trujillo-Estrada, Laura | Sanchez-Mejias, Elisabeth | del Rio, Juan Carlos | Torres, Manuel | Romero-Acebal, Manuel | Ruano, Diego | Vizuete, Marisa | Vitorica, Javier | Gutierrez, Antonia
Article Type: Research Article
Abstract: Here we demonstrated that extracellular, not intracellular, amyloid-β (Aβ) and the associated cytotoxic glial neuroinflammatory response are major contributors to early neuronal loss in a PS1xAPP model. A significant loss of principal (27%) and SOM/NPY (56–46%) neurons was found in the entorhinal cortex at 6 months of age. Loss of principal cells occurred selectively in deep layers (primarily layer V) whereas SOM/NPY cell loss was evenly distributed along the cortical column. Neither layer V pyramidal neurons nor SOM/NPY interneurons displayed intracellular Aβ immunoreactivity, even after formic acid retrieval; thus, extracellular factors should be preferentially implicated in this selective neurodegeneration. Amyloid …deposits were mainly concentrated in deep layers at 4–6 months, and of relevance was the existence of a potentially cytotoxic inflammatory response (TNFα, TRAIL, and iNOS mRNAs were upregulated). Moreover, non-plaque associated activated microglial cells and reactive astrocytes expressed TNFα and iNOS, respectively. At this age, in the hippocampus of same animals, extracellular Aβ induced a non-cytotoxic glial activation. The opposite glial activation, at the same chronological age, in entorhinal cortex and hippocampus strongly support different mechanisms of disease progression in these two regions highly affected by Aβ pathology. Show more
Keywords: Alzheimer's disease, amyloid, entorhinal cortex, microglia, neurodegeneration, neuroinflammation, transgenic
DOI: 10.3233/JAD-2009-1192
Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 755-776, 2009
