The accumulation of amyloid beta (A?) in the brain is a key element in the pathogenesis of Alzheimer?s disease. Cervical lymphatic vessels and the deep cervical lymph nodes are important elements of the lymphatic route of elimination of solutes from the brain, including A?. Our studies have shown that aging diminishes lymphatic contractile frequency, lymphatic tone and lymph flow, which in combination with a pro-inflammatory, high- histamine environment in perilymphatic tissues drives the functional impairment of brain-draining cervical lymphatic vessels during aging, though the degree of impairment is not the same in every aged individual. Clinical studies have shown that the presence of chronic local or systemic inflammation in the elderly increases the likelihood of developing Alzheimer?s disease. A common feature of inflammatory diseases is excessive mast cell degranulation (i.e., above the elevated levels observed in ?healthy aging?), which is associated with high levels of histamine throughout the body. In contrast to healthy aging, where histamine is released in moderate levels and maintains adequate lymphatic contractions and tone, high histamine levels observed during chronic inflammation/allergy inhibit lymphatic contractility/pumping. Thus, inhibition of mast cell degranulation (i.e. mast cell stabilization) may block excessive histamine release, thus preserving the cervical lymphatic vessels contractile function and cervical lymphatic clearance of A? from the brain. Therefore, the central hypothesis is that chronic inflammation-induced elevation of mast cell-derived histamine critically diminishes lymph flow in aged cervical lymphatic vessels, resulting in persistently decreased cervical lymphatic clearance of A? from brain and accelerated progression of Alzheimer?s disease.
The specific aims of project are:
Aim 1. To establish mechanistic links between chronic inflammation, cervical lymphatic clearance of A?, and Alzheimer?s disease-like progression in mice modeling Alzheimer?s disease.
Aim 2. To evaluate the mechanistic role of mast cell degranulation in Alzheimer?s disease-like progression in mice modeling Alzheimer?s disease under conditions of chronic inflammation. Our studies will provide the first quantitative measures of the cervical lymphatic A? clearance and will define the role of cervical lymphatic vessels and nodes in A? clearance and the regulation of brain A? levels. We will also identify chronic inflammation-associated mechanisms that impair this process. Thus, the proposed research will yield novel information on the mechanisms and impact of cervical lymphatic clearance of A? that will significantly expand our understanding of the pathogenesis of Alzheimer?s disease. Further, our studies are significant because lymph transport of brain- relevant molecules, including A?, is understudied as are the mechanisms that drive the disease-associated impairments of the cervical lymphatic system draining the brain. Our studies will provide innovative and readily translatable knowledge of the potential for mast cell stabilization as an approach to restore cervical lymphatic A? clearance, in order to treat Alzheimer?s disease.
The goal of the present proposal is to define the role of impaired cervical lymphatic clearance of amyloid beta (A?) in the pathogenesis of Alzheimer?s disease, while our translational goal is to lay the groundwork for the identification of specific therapeutic targets that mediate the impaired cervical lymphatic clearance of A? in Alzheimer?s disease. We propose that chronic inflammation-induced elevation of mast cell-derived histamine critically diminishes lymph flow in aged cervical lymphatic vessels, resulting in persistently decreased cervical lymphatic clearance of A? from brain and accelerated progression of Alzheimer?s disease. Studies will provide the first quantitative measures of the cervical lymphatic A? clearance and will define the role of cervical lymphatic vessels and nodes in A? clearance and the regulation of brain A? levels; they will also identify chronic inflammation-associated mechanisms that impair this process, so the proposed research will yield novel information on the mechanisms and impact of cervical lymphatic clearance of A? that will significantly expand our understanding of the pathogenesis of Alzheimer?s disease and will provide innovative and readily translatable knowledge of the potential for mast cell stabilization as an approach to restore cervical lymphatic A? clearance, in order to treat Alzheimer?s disease.
