Enhanced interstitial fluid drainage in the hippocampus of spontaneously hypertensive rats

Abstract

Hypertension is associated with cognitive decline and various forms of dementia, including Alzheimer’s disease. In animal models of hypertension, many of Alzheimer’s disease characteristics are recapitulated, including brain atrophy, cognitive decline, amyloid β accumulation and blood brain barrier dysfunction. Removal of amyloid β and other waste products depends in part on clearance via the brain interstitial fluid (ISF). Here we studied the impact of hypertension on ISF drainage, using spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). At 8 months, high (500 kD) and low (3 kD) fluorescent molecular weight tracers released passively into the hippocampus showed a drastically enhanced spreading in SHR. Tracer spreading was inhomogeneous, with accumulation at ISF-CSF borders, around arteries, and towards the stratum lacunosum moleculare. These locations stained positively for the astrocyte marker GFAP, and aquaporin 4. Despite enhanced dispersion, clearance of tracers was not affected in SHR. In conclusion, these data indicate enhanced bulk flow of ISF in the hippocampus of hypertensive rats. ISF drains along astrocytes towards the cerebrospinal fluid compartment, which leads to sieving of high molecular weight solutes. Sieving may lead to a local increase in the concentration of waste products and potentially promotes the aggregation of amyloid β.

Rapid actions of anti‐Müllerian hormone in regulating synaptic transmission and long‐term synaptic plasticity in the hippocampus

“…15,16 Therefore, hippocampal Amh has the potential to act as a paracrine factor via the CSF circulation in regulating functions of other brain structures, such as the hypothalamus which is known to express Amhr2. Because circulating Amh produced by the gonads does not cross the blood-brain barrier, 14 the CSF Amh is predominantly generated locally in the central nervous system.…”

Understanding the functions and relationships of the glymphatic system and meningeal lymphatics

“…Further, it is possible that there was retrograde flow of tracer along the cannula track into the subarachnoid CSF, suggesting that periarterial tracer was due to glymphatic CSF influx rather than ISF efflux. Finally, as shown in a recent study by Bedussi and colleagues, the appearance of tracer in a periarterial distribution may result from pressure injection of tracer into brain tissue immediately adjacent to an artery, rather than occurring as a consequence of true ISF bulk flow (31). Based on these findings, however, it was postulated that once within the arterial wall, parenchymal solutes travel in a direction opposite to blood flow toward larger and more proximal vessels until they ultimately reach the internal cerebral artery (ICA), where solute can be drained by deep cervical lymph nodes (dcLNs) (30,32,33).…”

Paravascular spaces: entry to or exit from the brain?

“…Several studies showed endothelial dysfunction in cerebral vessels of hypertensive animals (Baumbach & Heistad, ), which might affect the integrity of the BBB. We speculated that this could lead to increased ISF formation, a notion that was supported by increased spreading of tracers released into the hippocampus (Bedussi, Naessens, et al, ). However, more recent work from our group showed that the BBB and blood–CSF barrier function of spontaneously hypertensive rats is still intact with respect to the permeability to small solutes, such as fluorescein (Naessens et al., ).…”

“…Several studies showed endothelial dysfunction in cerebral vessels of hypertensive animals (Baumbach & Heistad, 1988), which might affect the integrity of the BBB. We speculated that this could lead to increased ISF formation, a notion that was supported by increased spreading of tracers released into the hippocampus (Bedussi, Naessens, et al, 2017).…”

“…Overt leakiness might be present only in specific areas, including the paraventricular nucleus and brainstem (Biancardi, Son, Ahmadi, Filosa, & Stern, 2014;Buttler et al, 2017;Setiadi, Korim, Elsaafien, & Yao, 2018). Nonetheless, there is a remarkable similarity between sites of tracer accumulation and sites of amyloid-deposition in rodents (Bedussi, Naessens, et al, 2017). This suggests that barriers formed by astrocytes, including those around paravascular spaces around arteries, can act as a sieve that allows water to pass from the ISF to the CSF, whereas larger solutes tend to accumulate.…”