APOE4-APP interactions exert early influences on cerebrovascular structure and function: Implications for Alzheimer's Disease

Lanboling Guo¹Jessica R Gaunt¹Calvin Chee Hoe Cheah¹Albert I. Chen²Stephanie Claudine³Gavin Dawe³Eyleen Lay Keow Goh¹Sok-Hong Kho³Pawan Kumar³Grace G Y Lim¹Kah-Leong Lim¹Yun-An Lim³Takaomi Saido⁴Takashi Saito⁵Hiroki Sasaguri⁶Judy CG Sng³Yee Jie Yeap¹Alaric K K Yip¹Norliyana Zainolabidin¹Toh Hean Ch'ng¹George J. Augustine^1,7*

• ¹Neuroscience & Mental Health Program, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore, Singapore
• ²School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
• ³Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
• ⁴RIKEN Center for Brain Science, Saitama, Japan, Saitama, Japan
• ⁵Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
• ⁶Dementia Pathophysiology Collaboration Unit, RIKEN Center for Brain Science, Wako, Japan
• ⁷Temasek Life Sciences Laboratory, Singapore, Singapore

Background: APOE4 and APP are two of the main genetic risk factors for Alzheimer's disease (AD). Although there have been suggestions that these two factors interact, most of the in vivo evidence for such interactions comes from transgenic mouse models that suffer from complications associated with protein overexpression. Our goal was to examine the consequences of interactions between APOE4 and APP on brain function while avoiding the use of transgenic mice. Methods: We generated and characterized double-mutant knock-in mice incorporating familial APP mutations and humanized APOE4. Results: In the brains of 3-month-old double-mutant mice there were significant alterations in vascular remodeling genes, vascular structure and blood-brain barrier permeability. These changes were not observed in either APOE4 or APP single-mutant mice and, thus, were caused by interactions between the two genes. These interaction effects were transient, because they were absent in 8-month-old double-mutant mice. Conclusions: These findings indicate that early vascular changes, driven by the interaction of APP and APOE4, may influence the progression of AD. Our work highlights the need to focus on the synergistic vascular actions of APOE4 and APP, particularly at younger ages.