Sandro Da Mesquita, PhD

Early on in my career, I developed a special interest for the cellular and molecular interactions happening at the border-like interfaces between the central nervous system (CNS) and the periphery. Currently, I am interested in advancing our understanding about the role of the meningeal lymphatic system in brain aging and in Alzheimer’s disease (AD).   As a graduate student, my attention was drawn to deciphering the role of the blood-cerebrospinal fluid (CSF) barrier, delimited by the choroid plexus (ChP) epithelium, in disease models with a strong neuroinflammatory component, namely experimental autoimmune encephalomyelitis and AD. In one of our publications (Da Mesquita et al, Brain Behav Immun., 2015), we have described progressive alterations in type I and II interferon (IFN) responses at the level of the ChP of aged and AD transgenic mice and shown that increased levels of a type I IFN cytokine, IFN-a, in the CSF was positively correlated with increased hippocampal astrogliosis and worse spatial learning and memory.   Recently, I have become fascinated with another neuro-immune interface: the meninges of the brain. As a postdoctoral research associate in the Kipnis lab, at the Department of Neuroscience of the University of Virginia, we have been focusing our attention on the recently characterized bona fide lymphatic vasculature that exists in the meninges of both rodents and humans and is closely involved in the drainage of both CSF macromolecules and meningeal immune cells into the peripheral cervical lymph nodes. In a recent publication (Da Mesquita et al, Nature, 2018) we have shown that: 1) decreased meningeal lymphatic drainage capacity leads to worse brain “function and poor cognitive performance in adult mice; 2) aging leads to meningeal lymphatic dysfunction and improving CSF drainage by meningeal lymphatics is beneficial for the aged brain; and 3) meningeal lymphatic dysfunction aggravates amyloid pathology in a transgenic mouse model of familial AD. 

Building on our most recent findings, we are currently addressing the following questions: 

• Is the efficiency of anti-amyloid beta immunotherapy affected by meningeal lymphatic drainage? 

• Is the meningeal immune response affected by decreased lymphatic drainage in aging? If so, do changes in the meningeal immune response impact on Alzheimer’s disease-associated brain pathological hallmarks? 

Taking into account my academic training, scientific background and the vital expertise acquired under the mentorship of Dr. Kipnis, I feel prepared to initiate a career as an independent investigator in academia. As an independent principal investigator, my lab will continue studying the molecular underpinnings of meningeal lymphatic dysfunction in the context of healthy or pathological aging. We will test the hypothesis that certain environmental (e.g. diet, exercise, infections) and genetic factors (e.g. APOE, TREM2, PICALM) increase the risk for AD by mediating long-lasting changes in the meningeal lymphatic vasculature and in the brain/meningeal immune responses. We will begin by developing strategies to decipher if, how and when dyslipidemia (induced by high-fat diet) and APOE genotype (alone or in combination) affect the meningeal lymphatic system, and whether this translates into defective immune response, brain cell function and behavioral performance (particularly cognition). Understanding how the meningeal lymphatic system becomes dysfunctional with aging will allow us to develop novel and better strategies to target this vascular system and to restore its capacity to drain both CSF solutes and immune cells. Restoring meningeal lymphatic function in aging and in AD might prove to be of great therapeutic value to control neuropathology, promote brain cell recovery and delay the appearance of cognitive deficits

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