Reversal of ApoE4-Driven Brain Pathology by Vascular Endothelial Growth Factor Treatment

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.

Markers of neuroinflammation associated with Alzheimer’s disease pathology in older adults

“…VEGF is expressed by neurons, microglia, astrocytes and endothelial cells, and was found within diffuse perivascular amyloid plaques in the brains of patients with AD (Merrill and Oldfield, 2005;Thirumangalakudi et al, 2006). It has been hypothesized that VEGF is secreted following stimulation by Aβ and may indicate a compensatory mechanism for the compromised vasculature and perfusion in the AD brain (Patel et al, 2010) (Salomon-Zimri et al, 2016.…”

Central and Peripheral Mechanisms in ApoE4-Driven Diabetic Pathology

“…Plasma and hippocampus samples were boiled for 10 min with 0.5% SDS and immunoblotted as previously described [71,109]. The following Abs were used: Mouse anti-IRβ (1:1000; Cell Signaling, Danvers, MA, USA), rabbit anti-IRβ (1:500; Cell Signaling, Danvers, MA, USA), rabbit anti-Akt (1:000; Cell Signaling, Danvers, MA, USA), rabbit anti-p Ser473 Akt (1:1000; Cell Signaling, Danvers, MA, USA), rabbit anti-p Thr308 Akt (1:1000; Cell Signaling, Danvers, MA, USA), mouse anti-GSK-3α/β (1:1000; Santa Cruz, Santa Cruz, CA, USA), mouse anti-p tyr216 GSK-3α/β (1:500; Santa Cruz, Santa Cruz, CA, USA), mouse anti-p Ser9 GSK-3β (1:1000; Santa Cruz, Santa Cruz, CA, USA), and goat anti-apoE (1:10,000; Millipore, Burlington, MA, USA).…”

Juvenile Traumatic Brain Injury Results in Cognitive Deficits Associated with Impaired Endoplasmic Reticulum Stress and Early Tauopathy

“…This may be the triggering event for acute cellular hypoxia and neuroinflammation, but further studies are warranted to prove this connection and investigate these pathways [61]. The timing of ER stress activation correlated with the upregulation of HIF-1α at 48 h. HIF-1α is a regulator of multiple intracellular pathways and has recently been shown to contribute to tau oligomer formation [62].…”