Here we demonstrated that extracellular, not intracellular, Aβ and the
associated cytotoxic glial neuroinflammatory response are major contributors of
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 (TNFalpha, TRAIL and iNOS mRNAs were
upregulated). Moreover, non-plaques associated activated microglial cells and
reactive astrocytes expressed TNFalpha and iNOS, respectively. At this age, in
the hippocampus of same animals the 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.
; Jiménez, Sebastián; Trujillo-Estrada, Laura Isabel
