Search

Late onset Alzheimer’s Disease (AD) is the most common form of dementia, affecting 40 million patients and countless families worldwide. AD is characterized by accumulation of amyloid beta (Aß) in the brain and central nervous system (CNS). A growing body of evidence indicates that while Aß production is unchanged, its clearance from the CNS is attenuated in late onset AD. Therefore, it is critical to determine how Aβ is cleared from the brain and if these processes differ in healthy and AD patients. Recently, two groups independently reported that a network of meningeal lymphatic vasculature participates in the clearance of solutes and macromolecules from the brain and cerebrospinal fluid of mice. However the presence of meningeal lymphatic vessels and their potential role in the clearance of Aß has not yet been defined in humans. Therefore, to determine if human meningeal lymphatic vessels absorb Aβ, we used immunofluorescence to examine superior sagittal sinus-associated dura mater tissue in a cohort of 21 patient samples including 6 subjects with no diagnosed dementia (control), 7 subjects with histopathologically confirmed AD, and 8 with diagnosis of mixed or other dementia. We found podoplanin (PDPN) positive, lumenized vessels in 19/21 patient samples, with 5/6 in control patients, 7/7 in AD patients and 7/8 in other or mixed dementia patients. These vessels were located in the dura mater, lateral to the superior sagittal sinus, and ranged from approximately 10 to 500 microns in diameter. Trace Aβ immunoreactivity was colocalized with podoplanin-positive vessels in 1/5 control, 1/7 AD, and 1/7 other or mixed dementia patients. Aß reactivity was found in meningeal blood vessels of 0/6 control, 1/7 AD, and 0/7 other or mixed dementia patients. To our knowledge, these data are the first to robustly support the existence of lymphatic vasculature in the human meninges. The data further suggest that Aß does not appear to widely deposit along wither these meningeal lymphatic or blood vessels, even among AD subjects.

Background and Purpose— Cytochrome P450 epoxygenase metabolizes arachidonic acid to epoxyeicosatrienoic acids (EETs). EETs are produced in the brain and perform important biological functions, including vasodilation and neuroprotection. However, EETs are rapidly metabolized via soluble epoxide hydrolase (sEH) to dihydroxyeicosatrienoic acids (DHETs). We tested the hypothesis that sEH gene deletion is protective against focal cerebral ischemia through enhanced collateral blood flow. Methods— sEH knockout (sEHKO) mice with and without EETs antagonist 14, 15 epoxyeicosa-5( Z )-enoic acid (EEZE) were subjected to 2-hour middle cerebral artery occlusion (MCAO), and infarct size was measured at 24 hours of reperfusion and compared to wild-type (WT) mice. Local CBF rates were measured at the end of MCAO using iodoantipyrine (IAP) autoradiography, sEH protein was analyzed by Western blot and immunohistochemistry, and hydrolase activity and levels of EETs/DHETs were measured in brain and plasma using LC-MS/MS and ELISA, respectively. Results— sEH immunoreactivity was detected in WT, but not sEHKO mouse brain, and was localized to vascular and nonvascular cells. 14,15-DHET was abundantly present in WT, but virtually absent in sEHKO mouse plasma. However, hydrolase activity and free 14,15-EET in brain tissue were not different between WT and sEHKO mice. Infarct size was significantly smaller, whereas regional cerebral blood flow rates were significantly higher in sEHKO compared to WT mice. Infarct size reduction was recapitulated by 14,15-EET infusion. However, 14,15-EEZE did not alter infarct size in sEHKO mice. Conclusions— sEH gene deletion is protective against ischemic stroke by a vascular mechanism linked to reduced hydration of circulating EETs.

The brain is unique among virtually all somatic organs in its lack of a conventional lymphatic vasculature.1–3 In the periphery, the lymphatic circulation facilitates the clearance of extracellular proteins and excess fluid from the interstitium, a role critical to tissue homeostasis and function.4,5 Yet within the brain, despite its complex architecture and high metabolic activity and neural cells’ sensitivity to changes in the extracellular environment, no specialized organ-wide anatomic structure has yet been identified that facilitates the efficient lymphatic clearance of extracellular solutes and fluid from the brain parenchyma. For small molecules and hydrophobic compounds, efflux across the blood–brain barrier is relatively unrestricted. Molecules that are substrates for specific blood–brain barrier transporters are also readily cleared from the brain.6,7 Other compounds must be cleared from the brain interstitium to the cerebrospinal fluid (CSF) compartment, where they are ultimately eliminated to the blood stream via arachnoid granulations or to peripheral lymphatics along cranial nerves.1,8,9 However, the distances between much of the brain tissue and the CSF compartments are too great for efficient clearance by simple diffusion, particularly for large molecules (such as peptides and proteins) with low diffusion coefficients.6 Rather, the clearance of these interstitial solutes from the brain is attributed to bulk flow, by which convective currents of interstitial fluid (ISF) sweep solutes along at a high rate that is largely independent of molecular size.1,2,6,7 In a controversial series of studies, Grady et al10,11 suggested that brain ISF may exchange with CSF along paravascular routes surrounding cerebral blood vessels. Because these findings seemed to be subsequently refuted by Cserr et al,12,13 such retrograde movement of CSF into the brain parenchyma is now thought to …