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.
Highlights
Microvascular dysfunction, including impaired neurovascular coupling and blood brain barrier (BBB) disruption, occurs in both vascular dementia and Alzheimer’s Disease[1]
As the clearance of waste products, including amyloid β, from the brain parenchyma depends on transport via the interstitial fluid and subsequent removal via the BBB and paravascular pathways[14,15,16,17], we hypothesized that hypertension may alter fluid dynamics in the brain interstitium
Hypertensive rats were lighter than normotensive Wistar Kyoto rats (WKY) rats (Table 1)
Summary
Microvascular dysfunction, including impaired neurovascular coupling and blood brain barrier (BBB) disruption, occurs in both vascular dementia and Alzheimer’s Disease[1]. These changes may interfere with the clearance of potentially toxic waste products such as amyloid β, which are released in the brain interstitial fluid (ISF) and accumulate in the parenchyma and vessel walls[1]. In the present study we set out to determine the effect of hypertension on distribution and clearance of solutes via the interstitial fluid For this purpose, we studied the fate of fluorescent tracers released into the ISF of the hippocampus of normotensive and hypertensive rats
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