Extracellular Amyloid-β and Cytotoxic Glial Activation Induce Significant Entorhinal Neuron Loss in Young PS1^M146L/APP^751SL Mice

Article type: Research Article

Authors: Moreno-Gonzalez, Ines^{a; d} | Baglietto-Vargas, David^{a; d} | Sanchez-Varo, Raquel^{a; d} | Jimenez, Sebastian^{b; d; e} | Trujillo-Estrada, Laura^{a; d} | Sanchez-Mejias, Elisabeth^{a; d} | del Rio, Juan Carlos^b | Torres, Manuel^{b; d; e} | Romero-Acebal, Manuel^{c; d} | Ruano, Diego^{b; d; e} | Vizuete, Marisa^{b; d; e} | Vitorica, Javier^{b; d; e;} | Gutierrez, Antonia^{a; d; *;}

Affiliations: [a] Department of Biología Celular, Genética y Fisiología, Facultad de Ciencias, Universidad de Málaga, Spain | [b] Department of Bioquímica, Bromatologia, Toxicología y Medicina Legal, Facultad de Farmacia, Universidad de Sevilla, Spain | [c] Servicio de Neurología, Hospital Universitario Virgen de la Victoria, Málaga | [d] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain | [e] Instituto de Biomedicina de Sevilla (IBiS)-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Spain

Correspondence: [*] Address for correspondence: Antonia Gutierrez, PhD, Department of Biología Celular, Genética y Fisiología, Facultad de Ciencias, Universidad de Málaga, Campus de Teatinos, 29071, Málaga, Spain. Tel.: +34 952133344; Fax: +34 952131937; E-mail: [email protected].

Note: [1] Co-Senior Authors.

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.

Keywords: Alzheimer's disease, amyloid, entorhinal cortex, microglia, neurodegeneration, neuroinflammation, transgenic

DOI: 10.3233/JAD-2009-1192

Journal: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 755-776, 2009