Early astroglial and neuronal changes in the hippocampus of PDAPP-J20 transgenic mice, model of Alzheimer's disease.

BEAUQUIS J; POMILIO C; VINUESA A; PAVÍA P; GALVÁN V; SARAVIA F

San Diego

Congreso; 43rd Annual Meeting of the Society for Neuroscience; 2013

Society for Neuroscience

In the context of Alzheimer´s disease (AD), hippocampal alterations have been well described in advanced stages of the pathology, when widespread amyloid pathology is present and inflammatory changes and glial reactivity occur, but less attention has been directed to study early brain changes. In the present study, using an animal model of AD, the transgenic PDAPP-J20 mouse (carrying human APP gene with Swe and Ind familial AD mutations), we studied early alterations in astroglia and neurons. We evaluated transgenic (Tg) and control (NTg) mice at 5 months of age, when no amyloid plaques are present in the hippocampus and low cerebral levels of amyloid peptides are detectable. Astrocytes were studied using glial fibrillary acidic protein (GFAP) immunofluorescence, confocal imaging and stereology. In Tg mice, we found a reduction in the number of GFAP+ astrocytes in CA1 region along with a decrease in astrocytic three-dimensional complexity studied as a surface/volume index, contrasting the established notion of a generalized astrogliosis accompanying the neurodegenerative process. Regarding neuronal changes, we found significantly less number of NeuN+ neurons in CA1 pyramidal layer of Tg mice but no changes were detected in dendritic spine density studied by means of a Golgi study. We also analyzed the number and morphology of doublecortin+ (DCX) cells in the dentate gyrus to evaluate adult neurogenesis. Transgenic animals showed decreased numbers of DCX+ cells showing a mature as well as an immature morphology, although Tg animals had a relative shift towards a more mature morphology to the detriment of the immature population. These changes in adult-born neurons in the dentate gyrus correlated with a decrease in the expression of synaptophysin+ mossy fibers reaching CA3. Our data support the idea of premature loss of both neurons and astrocytes in the hippocampus of AD mice at an age when there are no evidences of extensive amyloid pathology. Both cell types appear as especially vulnerable at early stages of the pathology. Astroglial changes found in this study characterize an atrophic phenotype and a lost of glial support could explain the neuronal changes found at this age, although a primary neuronal alteration cannot be discarded.