Fight Aging!

Cerebrospinal fluid is produced constantly, circulates through the brain, and drains into the body. This flow carries metabolic waste from the brain, and researchers are coming to view the age-related impairment of cerebrospinal fluid drainage as an important contribution to loss of cognitive function and the development of neurodegenerative conditions in later life. Several pathways for drainage have been identified, each of which is known to lose function with advancing age.

Firstly, cerebrospinal fluid drains through holes in the cribriform plate behind the nose. This pathway ossifies and closes up with age or injury. Studies conducted by Leucadia Therapeutics have added a weight of evidence to the importance of impairment of this fluid drainage path to the development of Alzheimer's disease, which begins in a part of the brain specifically served by cribriform plate drainage. Secondly, the glymphatic system drains cerebrospinal fluid into lymphatic vessels. The meninges, the layered membrane surrounding the brain and spinal cord, is lined with lymphatic vessels and fluid passes into them from the brain. This system of vessels suffers atrophy and dysfunction with age, just like the rest of the lymphatic system. Analogies can be made to the decline of the vasculature for blood flow throughout the body; the density of small capillary vessels declines with age as the processes of maintenance and creation of new vessels become dysfunctional.

In today's open access paper, researchers show that this analogy holds for the approach of provoking increased vessel creation as a way to address the age-related loss of small vessels. It has been demonstrated that upregulation of VEGF via gene therapy improves angiogenesis in older mice. It also improves late-life health, likely in part by removing some of the loss of capillary density. For lymphatic vessels, the analogous signaling protein to promote generation of new vessels is VEGF-C. Here, researchers demonstrate that delivering VEGF-C as a gene therapy to the the meninges can restore cerebrospinal fluid drainage in old mice, and also improve measures of brain function. They show that inflammatory signaling in the brain is reduced once drainage is improved, lending support to the view that the whole problem of reduced drainage is that an increase in metabolic waste in the brain provokes a maladaptive inflammatory response from microglia, innate immune cells of the central nervous system.

Meningeal lymphatics-microglia axis regulates synaptic physiology

Meningeal lymphatic vessels, located in the dura mater of the meninges, drain cerebrospinal fluid (CSF) together with its content of central nervous system (CNS)-derived waste primarily into deep cervical lymph nodes. Since the discovery of meningeal lymphatic vessels, accumulating evidence from mouse models and humans has linked their dysfunction to various neurodegenerative conditions. Ablation of meningeal lymphatics by chemical, genetic, or surgical means exacerbates behavioral outcomes in mouse models of Alzheimer's disease, traumatic brain injury, and chronic stress. Conversely, enhancing the function of meningeal lymphatics ameliorates cognitive deficits in mouse models of Alzheimer's disease, aging, and craniosynostosis.

Here, we show that prolonged impairment of meningeal lymphatics alters the balance of cortical excitatory and inhibitory synaptic inputs, accompanied by deficits in memory tasks. These synaptic and behavioral alterations induced by lymphatic dysfunction are mediated by microglia, leading to increased expression of the interleukin 6 gene (Il6). IL-6 drives inhibitory synapse phenotypes. Restoring meningeal lymphatic function in aged mice via intracisternal injection of adeno-associated virus encoding VEGF-C reverses age-associated synaptic and behavioral alterations. Our findings suggest that dysfunctional meningeal lymphatics adversely impact cortical circuitry through an IL-6-dependent mechanism and identify a potential target for treating aging-associated cognitive decline.