Blast-Mediated Traumatic Brain Injury Exacerbates Retinal Damage and Amyloidosis in the APPswePSENd19e Mouse Model of Alzheimer's Disease

• Published in: Investigative ophthalmology & visual science 2019-06, Vol.60 (7), p.2716-2725
• Main Authors: Harper, Matthew M, Hedberg-Buenz, Adam, Herlein, Judith, Abrahamson, Eric E, Anderson, Michael G, Kuehn, Markus H, Kardon, Randy H, Poolman, Pieter, Ikonomovic, Milos D
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - pathology; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - metabolism; Amyloidosis - metabolism; Amyloidosis - pathology; Animals; Blast Injuries - complications; Blast Injuries - metabolism; Blast Injuries - pathology; Brain - metabolism; Brain - pathology; Brain Injuries, Traumatic - complications; Brain Injuries, Traumatic - metabolism; Brain Injuries, Traumatic - pathology; Disease Models, Animal; Electroretinography; Female; Male; Mice; Mice, Transgenic; Optic Nerve - metabolism; Optic Nerve - pathology; Reflex, Pupillary - physiology; Retina; Retinal Diseases - etiology; Retinal Diseases - metabolism; Retinal Diseases - physiopathology; Retinal Ganglion Cells - metabolism; Retinal Ganglion Cells - pathology; Tomography, Optical Coherence
• ISSN: 1552-5783; 0146-0404; 1552-5783
• DOI: 10.1167/iovs.18-26353

Traumatic brain injury (TBI) is a risk factor for developing chronic neurodegenerative conditions including Alzheimer's disease (AD). The purpose of this study was to examine chronic effects of blast TBI on retinal ganglion cells (RGC), optic nerve, and brain amyloid load in a mouse model of AD amyloidosis. Transgenic (TG) double-mutant APPswePSENd19e (APP/PS1) mice and nontransgenic (Non-TG) littermates were exposed to a single blast TBI (20 psi) at age 2 to 3 months. RGC cell structure and function was evaluated 2 months later (average age at endpoint = 4.5 months) using pattern electroretinogram (PERG), optical coherence tomography (OCT), and the chromatic pupil light reflex (cPLR), followed by histologic analysis of retina, optic nerve, and brain amyloid pathology. APP/PS1 mice exposed to blast TBI (TG-Blast) had significantly lower PERG and cPLR responses 2 months after injury compared to preblast values and compared to sham groups of APP/PS1 (TG-Sham) and nontransgenic (Non-TG-Sham) mice as well as nontransgenic blast-exposed mice (Non-TG-Blast). The TG-Blast group also had significantly thinner RGC complex and more optic nerve damage compared to all groups. No amyloid-β (Aβ) deposits were detected in retinas of APP/PS1 mice; however, increased amyloid precursor protein (APP)/Aβ-immunoreactivity was seen in TG-Blast compared to TG-Sham mice, particularly near blood vessels. TG-Blast and TG-Sham groups exhibited high variability in pathology severity, with a strong, but not statistically significant, trend for greater cerebral cortical Aβ plaque load in the TG-Blast compared to TG-Sham group. When combined with a genetic susceptibility for developing amyloidosis of AD, blast TBI exposure leads to earlier RGC and optic nerve damage associated with modest but detectable increase in cerebral cortical Aβ pathology. These findings suggest that genetic risk factors for AD may increase the sensitivity of the retina to blast-mediated damage.