Association of Apolipoprotein E4-related Microvascular Disease in the Alzheimer’s Disease Hippocampal CA1 Stratum Radiatum

• Published in: Neuroscience Vol. 526; pp. 204 - 222
• Main Authors: Wang, Huaixing, Zhang, Zongxiu, Sittirattanayeunyong, Sorawit, Hongpaisan, Jarin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 21.08.2023
• Subjects: Alzheimer Disease - pathology; Alzheimer’s disease; Amyloid beta-Peptides - metabolism; Apolipoprotein E4 - genetics; Apolipoprotein E4 - metabolism; Apolipoproteins E; arteriolosclerosis; CA1 Region, Hippocampal - pathology; Echinomycin - metabolism; hippocampus; Hippocampus - metabolism; human brain microvascular cells; Humans; oxidative stress; Vascular Endothelial Growth Factor A - metabolism; APP; HBMECs; arteriolosclerosis; HIF-1α; E4; human brain microvascular cells; Aβ; 8-OHG; VEGFR; KD; ApoE; 8-OHdG; AC; AD; Alzheimer’s disease; hippocampus; VEGF; PKCε; DAPI; MV; Hu; Nac; MnTMPyP; MnSOD; ROS; TFAM; oxidative stress; ERK
• ISSN: 0306-4522; 1873-7544; 1873-7544
• DOI: 10.1016/j.neuroscience.2023.06.019

•Mild oxidative stress and VEGF reduction in capillaries of human AD hippocampus.•Strong oxidative stress, increased VEGF and wall cell number in AD + APOE4 arterioles.•Aβ decreases VEGF and human brain microvascular endothelial cell (HBMEC) density.•Aβ + ApoE4 increase strong oxidative stress, VEGF and cultured HBMEC cell density. Current data suggest a hypothesis of vascular pathogenesis for the development and progression of Alzheimer’s disease (AD). To investigate this, we studied the association of apolipoprotein E4 (APOE4) gene on microvessels in human autopsy-confirmed AD with and without APOE4, compared with age/sex-matched control (AC) hippocampal CA1 stratum radiatum. AD arterioles (without APOE4 gene) had mild oxidative stress and loss of vascular endothelial growth factor (VEGF) and endothelial cell density, reflecting aging progression. In AD + APOE4, an increase in strong oxidative DNA damage marker 8-hydroxy-2′-deoxyguanosine (8-OHdG), VEGF, and endothelial cell density were associated with increased diameter of arterioles and perivascular space dilation. In cultured human brain microvascular cells (HBMECs), treatment of ApoE4 protein plus amyloid-β (Aβ) oligomers increased superoxide production and the apoptotic marker cleaved caspase 3, sustained hypoxia inducible factor-1α (HIF-1α) stability that was associated with an increase in MnSOD, VEGF, and cell density. This cell over-proliferation was inhibited with the antioxidants N-acetyl cysteine and MnTMPyP, the HIF-1α inhibitor echinomycin, the VEGFR-2 receptor blocker SU1498, the protein kinase C (PKC) ε knock-down (KD) and the extracellular signal-regulated kinase 1/2 (ERK) inhibitor FR180204. The PKCε KD and echinomycin decreased VEGF and/or ERK. In conclusion, AD capillaries and arterioles in hippocampal CA1 stratum radiatum of non-APOE4 carriers are related with aging, while those in APOE4 carriers with AD are related with pathogenesis of cerebrovascular disease.