title: Extracellular amyloid-beta and cytotoxic glial activation induce significant entorhinal neuron loss in young PS1(M146L)/APP(751SL) mice.
abstract: Here we demonstrated that extracellular, not intracellular, amyloid-beta (Abeta) 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 Abeta 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 (TNFalpha, TRAIL, and iNOS mRNAs were upregulated). Moreover, non-plaque associated activated microglial cells and reactive astrocytes expressed TNFalpha and iNOS, respectively. At this age, in the hippocampus of same animals, extracellular Abeta 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 Abeta pathology.
authors: Department of Biología Celular, Genética y Fisiología, Facultad de Ciencias, Universidad de Málaga, 29071, Málaga, Spain.
authors: Ines
authors: I
authors: Moreno-Gonzalez
authors: David
authors: D
authors: Baglietto-Vargas
authors: Raquel
authors: R
authors: Sanchez-Varo
authors: Sebastian
authors: S
authors: Jimenez
authors: Laura
authors: L
authors: Trujillo-Estrada
authors: Elisabeth
authors: E
authors: Sanchez-Mejias
authors: Juan Carlos
authors: JC
authors: Del Rio
authors: Manuel
authors: M
authors: Torres
authors: Manuel
authors: M
authors: Romero-Acebal
authors: Diego
authors: D
authors: Ruano
authors: Marisa
authors: M
authors: Vizuete
authors: Javier
authors: J
authors: Vitorica
authors: Antonia
authors: A
authors: Gutierrez
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D016923:Cell Death; D018728:Entorhinal Cortex / Q000166:cytology / Q000473:pathology*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009457:Neuroglia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D016133:Polymerase Chain Reaction; D053764:Presenilin-1 / Q000235:genetics; D012313:RNA; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; D053764:Presenilin-1; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse