Sunday, May 11, 2025
5/11/2025
Investigation of cerebrovascular Notch as a novel modulator of cognitive function - Project Summary Alzheimer’s disease (AD) afflicts over 6 million people in the United States, and this number is expected to climb to nearly 13 million by 2050. The development of effective therapeutics is hampered not only by an incomplete understanding of the pathogenic cascades underlying AD development, but the challenges of identifying disease-modifying therapies that are also capable of blood-brain barrier penetrance. Increasing evidence implicates cerebrovascular dysfunction in the pathogenesis of AD, and cardiovascular risk factors such as obesity and diabetes increase the risk of late-onset AD up to two-fold. Brain microvascular endothelial cells (BMEC) act simultaneously as a barrier and interface between the central and peripheral environment and contribute to the regulation of processes such as neurogenesis and neuroinflammation via expression of angiocrine signaling factors. Dysregulation of neurogenesis and neuroinflammation are associated with AD pathology as well as obesity and diabetes. Notch proteins are part of an evolutionarily conserved signaling axis and play critical roles in the development and maintenance of vascular function. In the brain, dysregulation of endothelial Notch (EC-Notch) signaling leads to dysregulation of neurogenesis and blood-brain barrier integrity. Our preliminary studies have found that Notch signaling in the brain endothelium changes with age, is disrupted in AD, and inhibition of EC-Notch signaling is protective against AD-induced cognitive impairment. Although Notch is a well-described regulator of angiogenesis, we did not find overt changes in vascular morphology or density in response to Notch inhibition, suggesting that preservation of cognitive function may result from altered angiocrine signaling to neural cells. Alterations in Notch signaling are observed in response to, and modulate the course of, diet-induced obesity (DIO). Thus, dysregulation of EC-Notch signaling in response to DIO may present a mechanistic link between cardiovascular risk factors and AD pathology. This study will test the hypothesis that EC-Notch signaling contributes to the dysregulation of neuroinflammation and neurogenesis during AD and DIO-induced cognitive impairment. Using inducible genetic inhibition of EC-Notch, we will investigate its role in regulating adult hippocampal neurogenesis and neuroinflammation in a mouse model of AD, with the goal of identifying angiocrine signaling factors which mediate these effects. Because Notch signaling is influenced by, and capable of influencing, metabolic parameters such as obesity and insulin resistance, we will expand our studies to interrogate the role of EC-Notch in mediating cognitive impairment in response to DIO and insulin resistance. These studies will explore EC-Notch as a novel, common mechanism of cognitive decline in familial and late-onset AD and interrogate EC-Notch as a therapeutic target which does not require BBB penetration to exert influence on AD progression.
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