Reversal of ApoE4-Driven Brain Pathology by Vascular Endothelial Growth Factor Treatment
| Autor: | Anat Boehm-Cagan, Daniel M. Michaelson, Ori Liraz, Daniel Offen, Shiran Salomon-Zimri, Yael Barhum, Tali Ben-Zur, Micaela Johanna Glat, Ishai Luz |
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| Rok vydání: | 2016 |
| Předmět: |
Male
Vascular Endothelial Growth Factor A 0301 basic medicine Pathology medicine.medical_specialty Apolipoprotein E4 Genetic Vectors Apolipoprotein E3 Hippocampus Morris water navigation task Mice Transgenic tau Proteins Hippocampal formation Biology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Downregulation and upregulation mental disorders medicine Animals Humans LDL-Receptor Related Proteins Memory Disorders Amyloid beta-Peptides General Neuroscience Lentivirus Neurodegeneration Kinase insert domain receptor General Medicine Dependovirus Hypoxia-Inducible Factor 1 alpha Subunit medicine.disease Vascular Endothelial Growth Factor Receptor-2 Peptide Fragments Mice Inbred C57BL Vascular endothelial growth factor Disease Models Animal Psychiatry and Mental health Clinical Psychology Vascular endothelial growth factor A 030104 developmental biology chemistry Synapses Vesicular Glutamate Transport Protein 1 lipids (amino acids peptides and proteins) Geriatrics and Gerontology 030217 neurology & neurosurgery |
| Zdroj: | Journal of Alzheimer's Disease. 53:1443-1458 |
| ISSN: | 1875-8908 1387-2877 |
| DOI: | 10.3233/jad-160182 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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