Restore Meningeal Lymphatic Drainage to Alleviate White Matter Damage and Cerebral Amyloid Angiopathy in a Model of Alzheimer’s Disease

2023

Alzheimer’s disease (AD) is the most common form of dementia and represents a huge and growing socioeconomic burden to patients and their families worldwide. The increasing life expectancy and prevalence of AD heighten the urgency in understanding the pathophysiological mechanisms of this neurodegenerative disease and the need for better and personalized therapies. A common pathological feature of the AD brain is abnormal and deleterious inflammation, which is linked to the accumulation of toxic misfolded proteins, such as amyloid beta (Aβ), and activation of brain resident immune cells, namely the microglia. Often in AD cases, Aβ forms pathological aggregates around the blood vessels of the brain (giving rise to cerebral amyloid angiopathy, or CAA), which is accompanied by perivascular microglial activation and white matter damage and might result in microinfarcts and unwanted leakage of blood content into the brain. Using mouse models of AD-like brain amyloidosis, we have shown that an important vascular system that is involved in Aβ drainage from the brain, the meningeal lymphatic vasculature, also becomes dysfunctional with age. Importantly, our previous work pointed out that decreased brain drainage by the meningeal lymphatic system was linked to increased Aβ deposition and deleterious microglial activation. Our new preliminary data shows that the functional crosstalk between brain immune cells and the meningeal lymphatic system is reciprocal and that mice without microglia and abnormal immune cell activation also show a drastic defect in meningeal lymphatic vessels. In this research proposal, we will investigate how altered immune cell function and inflammation in the brain modulates the meningeal lymphatic system and whether restoring meningeal lymphatic drainage in combination with healthy microglia transplantation can further ameliorate brain Aβ deposition, white matter pathology, deleterious inflammation and vascular integrity in a mouse model of AD-like CAA.


Funding to Date

$201,250

Focus

Studies of Alternative Neurodegenerative Pathways, Translational

Researchers

Sandro Da Mesquita, Ph.D.