Cortical cerebrovascular and metabolic perturbations in the 5xFAD mouse model of Alzheimer's disease

Amandine Jullienne; Jenny I Szu; Ryan Quan; Michelle V Trinh; Tannoz Norouzi; Brenda P Noarbe; Amanda A Bedwell; Kierra Eldridge; Scott C Persohn; Paul R Territo; Andre Obenaus

doi:10.3389/fnagi.2023.1220036

Cortical cerebrovascular and metabolic perturbations in the 5xFAD mouse model of Alzheimer's disease

Front Aging Neurosci. 2023 Jul 18:15:1220036. doi: 10.3389/fnagi.2023.1220036. eCollection 2023.

Authors

Affiliations

¹ Department of Pediatrics, School of Medicine, University of California, Irvine, Irvine, CA, United States.
² Stark Neurosciences Research Institute, School of Medicine, Indiana University, Indianapolis, IN, United States.
³ Department of Medicine, School of Medicine, Indiana University, Indianapolis, IN, United States.

Abstract

Introduction: The 5xFAD mouse is a popular model of familial Alzheimer's disease (AD) that is characterized by early beta-amyloid (Aβ) deposition and cognitive decrements. Despite numerous studies, the 5xFAD mouse has not been comprehensively phenotyped for vascular and metabolic perturbations over its lifespan.

Methods: Male and female 5xFAD and wild type (WT) littermates underwent in vivo ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging at 4, 6, and 12 months of age to assess regional glucose metabolism. A separate cohort of mice (4, 8, 12 months) underwent "vessel painting" which labels all cerebral vessels and were analyzed for vascular characteristics such as vessel density, junction density, vessel length, network complexity, number of collaterals, and vessel diameter.

Results: With increasing age, vessels on the cortical surface in both 5xFAD and WT mice showed increased vessel length, vessel and junction densities. The number of collateral vessels between the middle cerebral artery (MCA) and the anterior and posterior cerebral arteries decreased with age but collateral diameters were significantly increased only in 5xFAD mice. MCA total vessel length and junction density were decreased in 5xFAD mice compared to WT at 4 months. Analysis of ¹⁸F-FDG cortical uptake revealed significant differences between WT and 5xFAD mice spanning 4-12 months. Broadly, 5xFAD males had significantly increased ¹⁸F-FDG uptake at 12 months compared to WT mice. In most cortical regions, female 5xFAD mice had reduced ¹⁸F-FDG uptake compared to WT across their lifespan.

Discussion: While the 5xFAD mouse exhibits AD-like cognitive deficits as early as 4 months of age that are associated with increasing Aβ deposition, we only found significant differences in cortical vascular features in males, not in females. Interestingly, 5xFAD male and female mice exhibited opposite effects in ¹⁸F-FDG uptake. The MCA supplies blood to large portions of the somatosensory cortex and portions of motor and visual cortex and increased vessel length alongside decreased collaterals which coincided with higher metabolic rates in 5xFAD mice. Thus, a potential mismatch between metabolic demand and vascular delivery of nutrients in the face of increasing Aβ deposition could contribute to the progressive cognitive deficits seen in the 5xFAD mouse model.

Keywords: MRI; PET; blood–brain barrier; cerebrovasculature; sex; vessels.

Grants and funding

The animal models in this study were whole or in part created by the Model Organism Development and Evaluation for Late-onset Alzheimer’s Disease (MODEL-AD) consortium funded by the National Institute on Aging. Relevant study strains and characterization data were generated by: the Indiana University/The Jackson Laboratory MODEL-AD Center U54 AG054345 led by Bruce T. Lamb, Gregory W. Carter, Gareth R. Howell, and PT and the University of California, Irvine MODEL-AD Center U54 AG054349 led by Frank M. LaFerla and Andrea J. Tenner. These resources were enhanced by: RF1 AG055104 to Michael Sasner, Gregory W. Carter, and Gareth R. Howell and U54 AG054349 S1-9 to Grant MacGregor, Kim N. Green, AO, Ian Smith, Xiangmin Xu, and Katrine Whiteson.