248-LB: Aging of Tanycytes Abolishes the Dynamic Regulation of Blood–Brain Barrier Permeability in the Hypothalamus

Abstract

Aberrant metabolic regulation and blood-brain barrier (BBB) dysfunction are two well-known phenomena of aging. The hypothalamus is the main brain region that controls food intake and body weight. It contains a specialized BBB that allows for the free flow of blood through fenestrated capillaries in the median eminence (ME), which places a portion of neurons critical to feeding unprotected by the BBB. Aging's pernicious effect on the traditional BBB throughout the brain is well studied, however how the specialized BBB in the hypothalamus is altered with age is unknown. To study the effects of aging on hypothalamic injury and repair, we injected monosodium glutamate (MSG) into young and old mice to ablate neurons located outside the BBB. We found that in the hypothalamus of young animals, MSG led to tightening of the BBB imparted by a reduction in the number of fenestrated capillaries. In contrast, aged mice were unable to dynamically alter the BBB permeability or modulate fenestrated blood vessels in response to MSG injury. We show that hypothalamic tanycytes, radial glial-like cells lining the wall of the third ventricle, show a higher degree of physical contact with fenestrated blood vessels than with non-fenestrated blood vessels. Tanycytes in young mice following MSG exposure, modified their expression of pleiotrophin, a growth and angiogenic factor, and robustly proliferated. In comparison, tanycytes in aged mice lacked in these responses to injury, which indicate these cells undergo functional decline with aging. Moreover, aged mice following MSG lost a greater number of neurons outside the BBB and experienced severe weight loss weeks after treatment, whereas young mice showed no change in their body weight. These findings uncover that aging leads to loss of hypothalamic BBB plasticity and defective tanycytes, which increase hypothalamic vulnerability to injury and morbidity development in aged animals. Disclosure V. Pham: None. A. Xu: Advisory Panel; Pennington Biomedical Research Center, Research Support; Eli Lilly and Company. T. P. Bachor: None. Funding National Institutes on Aging (1R01AG063506-01)