Title | Reversal of ApoE4-Driven Brain Pathology by Vascular Endothelial Growth Factor Treatment. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Salomon-Zimri, S, Glat, MJohanna, Barhum, Y, Luz, I, Boehm-Cagan, A, Liraz, O, Ben-Zur, T, Offen, D, Michaelson, DM |
Journal | J Alzheimers Dis |
Volume | 53 |
Issue | 4 |
Pagination | 1443-58 |
Date Published | 2016 Jun 30 |
ISSN | 1875-8908 |
Abstract | Apolipoprotein E4 (ApoE4), the most prevalent genetic risk factor for Alzheimer's disease (AD), is associated with increased neurodegeneration and vascular impairments. Vascular endothelial growth factor (VEGF), originally described as a key angiogenic factor, has recently been shown to play a crucial role in the nervous system. The objective of this research is to examine the role of VEGF in mediating the apoE4-driven pathologies. We show that hippocampal VEGF levels are lower in apoE4 targeted replacement mice compared to the corresponding apoE3 mice. This effect was accompanied by a specific decrease in both VEGF receptor-2 and HIF1-α. We next set to examine whether upregulation of VEGF can reverse apoE4-driven pathologies, namely the accumulation of hyperphosphorylated tau (AT8) and Aβ42, and reduced levels of the pre-synaptic marker, VGluT1, and of the ApoE receptor, ApoER2. This was first performed utilizing intra-hippocampal injection of VEGF-expressing-lentivirus (LV-VEGF). This revealed that LV-VEGF treatment reversed the apoE4-driven cognitive deficits and synaptic pathologies. The levels of Aβ42 and AT8, however, were increased in apoE3 mice, masking any potential effects of this treatment on the apoE4 mice. Follow-up experiments utilizing VEGF-expressing adeno-associated-virus (AAV-VEGF), which expresses VEGF specifically under the GFAP astrocytic promoter, prevented this effects on apoE3 mice, and reversed the apoE4-related increase in Aβ42 and AT8. Taken together, these results suggest that apoE4-driven pathologies are mediated by a VEGF-dependent pathway, resulting in cognitive impairments and brain pathology. These animal model findings suggest that the VEGF system is a promising target for the treatment of apoE4 carriers in AD. |
DOI | 10.3233/JAD-160182 |
Alternate Journal | J. Alzheimers Dis. |
PubMed ID | 27372644 |