Gial alterations from early to late stages in a model of Alzheimer?s disease: evidence of autophagy involvement in Aβ internalization

CARLOS POMILIO; PATRICIO PAVÍA; ROXANA MAYRA GOROJOD; ANGELES VINUESA; AGUSTINA ALAIMO; VERÓNICA GALVAN; MÓNICA LIDIA KOTLER; JUAN BEAUQUIS; FLAVIA E. SARAVIA

HIPPOCAMPUS

WILEY-LISS, DIV JOHN WILEY & SONS INC

Lugar: New York; Año: 2015

1050-9631

Alzheimer?s disease (AD) is a progressive neurodegenerativedisease without effective therapy. Brain amyloid deposits are classicalhistopathological hallmarks that generate an inflammatory reactionaffecting neuronal and glial function. The identification of early cellresponses and of brain areas involved could help to design new successfultreatments. Hence, we studied early alterations of hippocampal gliaand their progression during the neuropathology in PDAPP-J20 transgenicmice, AD model, at 3, 9, and 15 months (m) of age. At 3 m,before deposits formation, microglial Iba11 cells from transgenic micealready exhibited signs of activation and larger soma size in the hilus,alterations appearing later on stratum radiatum. Iba1 immunohistochemistryrevealed increased cell density and immunoreactive area inPDAPP mice from 9 m onward selectively in the hilus, in coincidencewith prominent amyloid Congo red1deposition. At pre-plaque stages,GFAP1 astroglia showed density alterations while, at an advanced age,the presence of deposits was associated with important glial volumechanges and apparently being intimately involved in amyloid degradation.Astrocytes around plaques were strongly labeled for LC3 until15 m in Tg mice, suggestive of increased autophagic flux. Moreover, b-Amyloid fibrils internalization by astrocytes in in vitro conditions wasdependent on autophagy. Co-localization of Iba1 with ubiquitin or p62was exclusively found in microglia contacting deposits from 9 monward, suggesting torpid autophagy. Our work characterizes glialchanges at early stages of the disease in PDAPP-J20 mice, focusing onthe hilus as an especially susceptible hippocampal subfield, and providesevidence that glial autophagy could play a role in amyloid processingat advanced stages.