Neuronal and Vascular Degeneration of the aging retina in the 3xTg-AD mouse


Alzheimer's disease (AD), a progressive and irreversible neurodegenerative disease and the most common cause of dementia in the United States, is characterized by amyloid β (Aβ) and tau deposition in the central nervous system (CNS), neurovascular dysfunction, and neuroinflammation. Diagnostic modalities to detect the early phases of these CNS pathologies in preclinical AD are inadequate. Vision abnormalities are common in AD, and Aβ and tau have been detected in the retina parallel to the brain. Noninvasive detection of early AD pathologies in the retina may enable: 1) improved understanding of the biologic foundation of AD, 2) early diagnosis and monitoring, 3) AD risk stratification, and 4) monitoring response to treatments. However, retinal structural or microvascular changes in AD, that may be detectable with noninvasive depth-resolved imaging modalities, have not been fully characterized yet. In this dissertation, several aspects of retinal neurovascular degeneration in a well-characterized mouse model of AD, 3xTg-AD, have been studied. Chapter one provides a rationale for studying retinal neurovascular alteration accompanying AD. Chapter two explores retinal sublayer thickness changes by optical coherence tomography (OCT) in young to middle age transgenic and control mice and suggests that a pattern of retinal sublayer changes may detect AD's preclinical stage and distinguish AD- from aging-neurodegeneration. The third chapter summarizes the age-dependent pattern of retinal capillary layer attenuation in the transgenic model. Such vascular degeneration may be due to amyloid and tau deposition in vessel walls and reduced metabolic demand caused by neuronal loss. Mapping out such retinal degenerative changes would aid in the noninvasive diagnosis of AD. In chapter four, a novel retinal tissue preparation protocol to investigate retinal neuronal and vascular structures without cutting through the retina and disturbing the geometric correlation of various retinal regions is introduced. The final chapter summarizes the findings of the current project and its contributions to the field. In summary, these studies describe several aspects of retinal neuronal and vascular structures from young to middle age to old age in a well-characterized murine model of AD. Our findings highlight the need for a multi-modal imaging approach for early detection of AD.

Alzheimer's disease, retina, capillary, OCT, biomarker, imaging, lightsheet microscopy