The Laboratory of Dr. Naomi Sayre
About this Lab
Several factors can contribute to age-related decline in brain function or neurodegeneration, including lifestyle choices, genetic risk factors, and history of brain damage. We study how brain damage affects the aging brain and predisposes patients to cognitive decline or neurodegeneration. We particularly focus on processes which are affected by ischemic stroke and traumatic injury, however we are also interested in those processes which affect pathogenesis of neurodegenerative diseases such as Alzheimer’s Disease.
For example, stroke is a primary cause of long term disability, and patients with a history of stroke of have greater risk of cognitive decline. Recurrent strokes cause dementia in 30% of patients. Patients with a history of multiple concussions are more likely to have a post-mortem diagnosis of chronic traumatic encephalopathy (CTE), a neuropathological condition which can become evident in patients decades after the brain was damaged. Altogether, ongoing, long-term processes contribute to brain function with age. Our goal is to better understand those processes and so enable intervention for at-risk patients.
LRP1 as a player in brain health
A leading genetic risk factor for neurodegeneration and poor outcome after brain injury is expression of the E4 allele of Apolipoprotein (ApoE4). The majority of the population express ApoE3; this lipoprotein is responsible for carrying astrocyte-secreted cholesterol and throughout the cerebrospinal fluid for delivery to other neural cells. The lipoprotein is delivered into cells via interaction with low-density lipoprotein receptor (LDLR) protein family members and receptor mediated endocytosis. Our studies center on one important member of this family: LDLR-related protein 1 (LRP1). A clear, mechanistic explanation for how ApoE4 negatively influences brain health is lacking, but it might be found with a better understanding of LRP1. In addition to ApoE endocytosis, LRP1 functions in other capacities within the cell-notably as a mediator of cellular signaling and as a clearance receptor for several factors in the extracellular and plasma-membrane space. LRP1 is the primary clearance receptor for amyloid beta, which is strongly implicated in pathogenesis of Alzheimer’s disease. LRP1 similarly plays a role in enabling the propagation of misfolded tau within the brain, suggesting it can fundamentally alter the disease course of tauopathies such as chronic traumatic encephalopathy. Altogether, LRP1 likely plays an integral role in maintaining proteostasis and cellular signaling with aging. A primary theme of my research program involves understanding the key functions modulated by LRP1, and how such functions might be disrupted in the context of aging, brain injury, and neurodegeneration.
Contact Information
Dr. Naomi Sayre
Assistant Professor, Dept. of Neurosurgery
sayre@uthscsa.edu