(750.1) Increased Neurovascular Vulnerability to Mild Traumatic Brain Injury in a Mouse Model of Marfan Syndrome

Poster Board Number: E408

Tala Curry (University of Arizona College of Medicine-Phoenix, University of Arizona College of Medicine-Phoenix), Mary Barrameda (Midwestern University), Caitlin Bromberg (University of Arizona College of Medicine-Phoenix, University of Arizona College of Medicine-Phoenix), Maha Saber (University of Arizona College of Medicine, University of Arizona College of Medicine), Rachel Rowe (University of Colorado Boulder), Rayna Gonzales (University of Arizona College of Medicine), Theresa Thomas (University of Arizona College of Medicine, University of Arizona College of Medicine), Mitra Esfandiarei (Midwestern University)

Over 69 million traumatic brain injuries (TBIs) are reported annually worldwide, where the geriatric population are at greatest risk for prolonged morbidity and mortality. Cerebrovascular aging contributes to this increased vulnerability through extracellular matrix (ECM) impairment, vascular wall weakening and stiffening, blood-brain barrier (BBB) permeability, and exacerbated cytokine production, yet the mechanisms behind these contributions are minimally investigated. In order to study these targets efficiently and with minimal variability, an animal model presenting these cerebrovascular alterations is required. Fibrillin-1 (Fbn1) protein plays a role in elasticity and inflammation, and its mutation is known to lead to ECM impairment and vessel wall weakening induced by increased availability in transforming growth factor-b (TGF-b) and downstream production of matrix metalloproteinases (MMPs)-2/-9. In mice, this mutation induces vascular dysfunction by 6M of age and is a well-established model of Marfan Syndrome.

In this study, Fbn1+/- were utilized to test the hypothesis that Fbn1 mutation accelerates cerebrovascular rigidity, BBB permeability, and neurological alterations associated with aging, leaving the brain more vulnerable to diffuse TBI. In 6M- and 12M-old Fbn1+/- and C57BL/6 wildtype (WT) male and female mice, posterior cerebral artery (PCA) blood flow (n=8-10), PCA rupture point (N=3-5/group), BBB permeability (N=2-3/group), injury viability (N=5-8/group), neurobehavioral severity scale (NSS) outcomes (N=10-11/group), and microglial perturbation (N=1/group) were assessed.

Our data shows that 6M-old Fbn1+/- mice have decreased PCA blood flow (plt;0.05), compromised PCA wall strength (plt;0.05), increased BBB permeability (plt;0.05), and elevated NSS scores (plt;0.05) as compared to 6M-old WT, and similar to 12M-old WT mice. Preliminary investigation of iba-1 staining for microglia, a supported assessment of neuroinflammation, suggests increased microglial activation in 6M-old Fbn1+/- mice compared to age-matched WT mice. To investigate vulnerability to mild TBI (mTBI), varying pulse pressures (1.11-1.32atm) were applied to the brains of 6M-old WT (1.25-1.32atm) and Fbn1+/- (1.17-1.21atm ) mice using midline fluid percussion injury, where Fbn1+/- mice required lowered pressure to induce mTBI righting reflex times (5-10 minutes).

These data support that cerebrovascular aging contributes to outcome after TBI. Furthermore, this study demonstrates that Fbn1 mutation plays a critical role in the vulnerability of the aged brain to mTBI. Using this novel approach of a Marfan Syndrome mouse model that isolates cerebrovascular aging allows for the mechanistic study of potential Fbn1 downstream pathways that could serve as a therapeutic target for prevention and management of post-concussive symptoms.

Support or Funding Information

Valley_Research_Partnership-2232011, NIH-R15HL145646, NIH-R01NS100793