Extracellular amyloid-beta and cytotoxic glial activation induce significant entorhinal neuron loss in young PS1(M146L)/APP(751SL) mice.
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.
Moreno-Gonzalez
Ines
I
Department of Biología Celular, Genética y Fisiología, Facultad de Ciencias, Universidad de Málaga, 29071, Málaga, Spain.
Baglietto-Vargas
David
D
Sanchez-Varo
Raquel
R
Jimenez
Sebastian
S
Trujillo-Estrada
Laura
L
Sanchez-Mejias
Elisabeth
E
Del Rio
Juan Carlos
JC
Torres
Manuel
M
Romero-Acebal
Manuel
M
Ruano
Diego
D
Vizuete
Marisa
M
Vitorica
Javier
J
Gutierrez
Antonia
A
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
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