The Interstitial System of the Brain in Health and Disease

Abstract

The brain interstitial fluid (ISF) and the cerebrospinal fluid (CSF) cushion and support the brain cells. The ISF occupies the brain interstitial system (ISS), whereas the CSF fills the brain ventricles and the subarachnoid space. The brain ISS is an asymmetrical, tortuous, and exceptionally confined space between neural cells and the brain microvasculature. Recently, with a newly developed in vivo measuring technique, a series of discoveries have been made in the brain ISS and the drainage of ISF. The goal of this review is to confer recent advances in our understanding of the brain ISS, including its structure, function, and the various processes mediating or disrupting ISF drainage in physiological and pathological conditions. The brain ISF in the deep brain regions has recently been demonstrated to drain in a compartmentalized ISS instead of a highly connected system, together with the drainage of ISF into the cerebrospinal fluid (CSF) at the surface of the cerebral cortex and the transportation from CSF into cervical lymph nodes. Besides, accumulation of tau in the brain ISS in conditions such as Alzheimer's disease and its link to the sleep-wake cycle and sleep deprivation, clearance of ISF in a deep sleep via increased CSF flow, novel approaches to remove beta-amyloid from the brain ISS, and obstruction to the ISF drainage in neurological conditions are deliberated. Moreover, the role of ISS in the passage of extracellular vesicles (EVs) released from neural cells and the rapid targeting of therapeutic EVs into neural cells in the entire brain following an intranasal administration, and the promise and limitations of ISS based drug delivery approaches are discussed Key words: beta-amyloid, cerebrospinal fluid, extracellular matrix, extracellular vesicles, glymphatic system, interstitial fluid, phosphorylated tau contiguous glia, or the adjoining neurons and glia is also known as the extracellular space (ECS) [1-3].

Extracellular vesicles from human iPSC‐derived neural stem cells: miRNA and protein signatures, and anti‐inflammatory and neurogenic properties

“…These results are consistent with the findings observed with MSC‐derived EVs recently [22]. Such rapid incorporation of EVs in neural cells within deep brain areas likely reflects the speedy entry of EVs into the subarachnoid space via perineurial spaces around olfactory nerves passing through the cribriform plate and the subsequent transportation through CSF flow into the interstitial fluid in the interstitial spaces of the brain [99]. The anti‐inflammatory effects of hiPSC‐NSCs‐EVs could be determined from both in vitro and in vivo prototypes of inflammation.…”

Small Vessel Disease-Related Dementia: An Invalid Neurovascular Coupling?

“…In SVD, the emerging role of PVS, astrocytic endfeet, cerebral capillaries and veins, and venules stands on their possible role of drainage system around cerebral microvessels, acting as a canal for fluid transport, the exchange between CSF and ISF and clearance of unwanted products from the brain [356]. Therefore, the modification of this system produces deleterious effects, whose results are an accumulation of catabolites and toxic substances, together with a great impoverishment of neural nutrition [357][358][359]. The enlargement and widening of PVS, lead a consequent leakage of fluid and plasma cells due to an obstructive process maintained by catabolites, proteins, and cell debris [35], together with the disruption of the BBB, which might eventually potentiate the perivascular inflammation, and all of the cascades of the inflammatory/obstructive/stagnation-induced process [360][361][362].…”

microRNA-Based Biomarkers in Alzheimer’s Disease (AD)

“…As the name suggests ECFs have been shown as being representative of the saline-based biofluids surrounding individual brain cell types (Alexandrov et al, 2012;Pogue et al, 2014;Shetty and Zanirati, 2020). ECF, sometimes referred to as interstitial fluid (ISF), drains through very narrow intercellular spaces within gray matter into bulk flow perivascular channels that surround penetrating arteries and then flows to the surface of the brain to join the CSF that drains into cervical lymph nodes (Shetty and Zanirati, 2020;Upadhya et al, 2020;Weller, 2020). Human brain CSF, produced by the choroid plexus and secreted into the brain ventricles and subarachnoid space, plays critical roles in the biophysical and immune protection of the brain and provides intra-cerebral transport of nutrients, cofactors and hormones, as well as small signaling molecules such as sncRNAs and miRNAs.…”

“…Human brain CSF, produced by the choroid plexus and secreted into the brain ventricles and subarachnoid space, plays critical roles in the biophysical and immune protection of the brain and provides intra-cerebral transport of nutrients, cofactors and hormones, as well as small signaling molecules such as sncRNAs and miRNAs. Since ECF and CSF circulates throughout and within the entire CNS: (i) ECF and CSF composition is representative of the biofluids surrounding both brain cells and multiple anatomical regions of the brain and spinal cord; and (ii) provides valuable insight into soluble pathogenic bio-markers that bathe CNS cells and tissues, including soluble miRNAs that have diagnostic value for human brain health, disease or injury (Hampel et al, 2018a,b,c;Shetty and Zanirati, 2020;Weller, 2020). Human peripheral blood serum is defined as the clear-yellowish fluid that remains from blood plasma after clotting factors (such as fibrinogen and prothrombin) have been removed after clot formation and whole blood centrifugation, and contains the same components as plasma such as fatty acids, hormones, cytokines, chemokines, carbohydrates, growth factors, and miRNAs (both free miRNAs and those packaged into extracellular vesicles) and is the circulating carrier of exogenous and endogenous fatty acids, free lipids and lipoproteins in the systemic circulation (Hill, 2019;Penner et al, 2019;Lukiw and Pogue, 2020;Shetty and Zanirati, 2020 7 ; last accessed 26 August 2020).…”

“…Interestingly in miRNA abundance analysis of Aβ-peptide stressed human neuronalglial (HNG) cell primary co-cultures, ECF displayed an upregulation of these same miRNAs, an effect that was quenched using anti-NF-kB agents CAPE and CAY10512. Overall the results indicated that these same microRNAs including miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a, and miRNA-155 are brain tissue-, CSF-and ECF-abundant, NF-kB-sensitive pro-inflammatory miRNAs, and their enrichment in both tissues and circulating AD biofluids suggest that they may be involved in the modulation or proliferation of miRNA-triggered pathogenic signaling throughout the human brain and CNS (Alexandrov et al, 2012;Hill, 2019;Lukiw and Pogue, 2020;Shetty and Zanirati, 2020).…”