| First Author | Baldassarro VA | Year | 2017 |
| Journal | Dis Model Mech | Volume | 10 |
| Issue | 5 | Pages | 671-678 |
| PubMed ID | 28237964 | Mgi Jnum | J:242040 |
| Mgi Id | MGI:5904230 | Doi | 10.1242/dmm.028001 |
| Citation | Baldassarro VA, et al. (2017) Vulnerability of primary neurons derived from Tg2576 Alzheimer mice to oxygen and glucose deprivation: role of intraneuronal amyloid-beta accumulation and astrocytes. Dis Model Mech 10(5):671-678 |
| abstractText | Microvascular dysfunction is considered an integral part of Alzheimer disease (AD) pathogenesis, but the possible relationship between amyloid pathology, microvascular dysfunction and cell death is still unclear. In order to investigate the influence of intraneuronal amyloid-beta (Abeta) accumulation on vulnerability to hypoxia, we isolated primary cortical neurons from Tg2576 (carrying the amyloid precursor protein APPSwe mutation) and wild-type fetal mice. We first demonstrated that neurons isolated from Tg2576 newborn mice show an increase in VEGFa mRNA expression and a decrease in the expression of the two VEGF receptors, Flt1 and Kdr, compared with wild-type cells. Moreover, APPSwe primary neurons displayed higher spontaneous and glutamate-induced cell death. We then deprived the cultures of oxygen and glucose (OGD) as an in vitro model of hypoxia. After OGD, APPSwe neurons display higher levels of cell death in terms of percentage of pyknotic/fragmented nuclei and mitochondrial depolarization, accompanied by an increase in the intraneuronal Abeta content. To explore the influence of intraneuronal Abeta peptide accumulation, we used the gamma-secretase inhibitor LY450139, which showed that the reduction of the intracellular amyloid fully protects APPSwe neurons from OGD-induced degeneration. Conditioned medium from OGD-exposed APPSwe or wild-type astrocytes protected APPswe neurons but not wild-type neurons, during OGD. In conclusion, the presence of the mutated human APP gene, leading to the intracellular accumulation of APP and Abeta fragments, worsens OGD toxicity. Protection of APPSwe neurons can be obtained either using a gamma-secretase inhibitor or astrocyte conditioned medium. |
