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In this study, we sought out significant changes in gene expression between control and AD CP tissue for genes that play key roles in CSF homeostasis. The BCSFB is a critical barrier interface that facilitates the regulated exchange of ion, hormones, vitamins, and trophic factors between the blood and CSF. The CP is capable of dynamic response to compensate for perturbations in the CSF solute homeostasis and neural tissue damage through secretions into the CSF (CITE). Communication between the immune system and the brain occurs at the BCSFB interface and at interfaces between the CSF and the brain. Glial cell signaling in response to neuroinflammation occurs via the CSF.
Degeneration of the CPE and CP metabolism in AD due to structural damage and oxidative stress compromises the integrity of the BCSFB and the composition of the CSF. Research has shown degradation of CPE tight junctions and dysregulated cholesterol metabolism associated with marked decline in amyloid-beta clearance from the CSF (CITE Johanson review). In addition, such damage harms the ability of the BCSFB to respond to neuroinflammation, and impairs the CP ability to mitigate neural damage in other brain areas, resulting in a vicious cycle. The results of our analysis of two GEO databases revealed alterations in gene expression in AD CP that suggest considerable changes to CSF solute homeostasis and CP secretory function. Whether or not these changes are cause or effect with respect to AD remain to be determined.
As discussed earlier, without an intact BCSFB, proper CSF homeostasis cannot be maintained even if CPE secretory potential remains intact. In accordance with this concept, we noted significant downregulation of claudin-5 in AD CP, an integral membrane protein and critical component of tight junction strands (CITE). In this way, claudin-5 serves as a gatekeeper protein facilitating regulated paracellular transport across BCSFB tight junctions, and downregulation of claudin-5 is a key indication of increased BCSFB permeability. Upregulation of proteins of the amyloid-beta precursor protein family APBA3 and APBB1IP correlate with the buildup of amyloid-beta plaques in the brain and in the CSF even as our data displayed a decrease in amyloid beta precursor protein expression in AD CP. Buildup of amyloid-beta in the CP and CSF without sufficient clearance due to damaged CPE and BCSFB integrity further damages the BCSFB by weakening tight junctions, exacerbating the damage done by claudin-5 downregulation (CITE).
Neuroinflammation is a hallmark of many neurodegenerative conditions including AD. Extensive tissue damage in the CPE due to inflammation will have an adverse effect on the CP ability to maintain homeostatic levels of solute transport into and out of the CSF and ventricular lumen. Our findings reported significant upregulation of the interleukin-1 receptor (IL1R) and the interleukin-1 receptor like 1 (IL1RL1), signals of extensive CPE inflammatory damage that likely will have an impact on CSF production. Among the cytokine families, the IL1 and IL1R families play important roles in the progression of both acute and chronic inflammation (CITE). Furthermore, IL1 has been implicated in ischemic brain injury due to stroke and subarachnoid hemorrhage (CITE) Antagonists raised against the IL1 receptors have been proven to be potent anti-inflammatory agents, and experiments in rats have shown certain concentrations of IL1R antagonists to be neuroprotective (CITE).
We proceeded to investigate other genes involved in neurodegenerative conditions that could impact the health of the CP. Presenilin 1 and 2 (PSEN1 and PSEN2) are key genes involved in the neuropathology of AD. Prior work has associated increases in PSEN1 and PSEN2 expression with increases in amyloid-beta plaque formation and decreased amyloid-beta clearance (CITE Wostyn 1). Furthermore, experiments that suggested caffeine provides a degree of protection against cognitive impairments during aging in AD-transgenic mice showed decreased levels of PSEN1 and PSEN2 expression in those mice (CITE Wostyn 2).
In those same experiments, CSF production increased in long term in rats given caffeine, accompanied by more efficient clearance of amyloid-beta and further decreases in PSEN1 and PSEN2 expression. Based on this work, there seems to be a correlation between PSEN1/2, CSF production, and amyloid beta clearance. While mining our GEO database, we found upregulation of PSEN1 and PSEN2 in AD CP, consistent with a model of presenilin genes playing principle roles in AD. Given the results of the caffeine experiments in rats, it is quite possible that high levels of PSEN1 and PSEN2 are in part responsible for the CSF production decreases seen in AD.
The clusterin family is another gene group thought to impact neurodegenerative conditions, ranging from AD to Parkinson’s Disease and Lewy Bodies. Specifically in AD, clusterin levels are increased in brain areas most severely affected by AD pathology (CITE Lidstrom). Clusterin is thought to assist with wound healing, possibly as a supplementary regenerative response initiated by AD damage. Curiously, our GEO database search revealed considerable decreases in clusterin-family gene expression levels in AD CP versus controls (downregulated clusterin, clusterin-like 1, and clusterin-associated protein 1). These findings are even more interesting in the context of clusterin levels in AD CSF, which have been shown to be on par with normal CSF clusterin levels (CITE Lidstrom). The exact impact of clusterin on CP function has yet to be determined.
Solute transport across the CPE drives the production of CSF. Proper solute concentrations allow the CSF to properly circulate nutrients in the brain, protect neurons from inflammatory damage, and facilitate the regrowth and repair of damaged neurons in response to trauma and brain injury (CITE). Moreover, homeostatic solute concentrations in the CSF allow for CSF control of homeostatic levels of brain temperature, blood pressure, and blood pH (CITE). For these reasons, we investigated several key solute transporters located in the CPE, with the most prominent transporter genes being those of the sodium-potassium ATPase family and the solute carrier group family. We considered both passive and active solute transporters, although special significance was given to the genes responsible for the active transport of cations and anions. Those particular genes represent the final pathway for CSF production, and so may be considered rate-limiting genes.
The structure of the sodium-potassium ATPase is as follows: a heterodimer of one alpha and one beta subunit, of which four different alpha subunits and three different beta subunits have been identified in mammals (CITE). ATP and cation binding sites are located on the membrane-spanning alpha subunit, which is responsible for the exchange of three sodium ions into the cell and two potassium ions out of the cell per molecule of ATP hydrolyzed. The beta subunit is a single-spanning membrane protein (the alpha subunit is multi-spanning), and does not contain any cation or ATP binding sites yet is still required for proper functioning of the ATPase pump.
Earlier work has shown considerable reductions in CSF secretion after inhibition of the sodium-potassium ATPase. This is predictable given the sodium-potassium ATPase role as the central pathway for sodium secretion into the CSF (and the central pathway for potassium clearance from the CSF). We report significant downregulation of four subunits of the sodium-potassium ATPase in AD: ATP1A2, ATP1B1, ATP1B2, and ATP1A4. One sodium-potassium ATPase subunit, ATP1A1, displayed mild upregulation in AD. The net result of these findings, expression levels of more subunits downregulated than upregulated, would imply a reduction in sodium-potassium ATPase function in AD and impairment of the major sodium-potassium exchange pathway, with decreased CSF production as the likely final consequence.
Many other cation and anion exchangers in addition to the sodium-potassium ATPase expressed in the CP belong to the solute carrier group gene family. One important transporter within this group that we investigated was the sodium-potassium-chloride cotransporters NKCC1 and NKCC2, encoded by the genes SLC12A2 and SLC12A1 respectively. NKCC1 has been localized to the apical CPE (CITE Brown). Evidence has historically been mixed as to whether or not NKCC1 mediates influx or efflux of ions, but a recent paper provides convincing evidence based on Gibbs free energy analysis for NKCC1 being an ion efflux transporter (CITE). In other words, NKCC1 facilitates the flow of sodium, potassium, and chloride ions from the CPE into the ventricular lumen. Such a finding, if reaffirmed, would support the argument that NKCC1 acts as a direct contributor to CSF production. In contrast, NKCC2 has been thought to be localized to the kidney. However, the GEO databases that we mined provide reason to believe that NKCC2 is present in the CPE, although its localization remains unknown.
Work by Steffensen has suggested that NKCC1 alone is responsible for almost fifty percent of CSF production, primarily due to its central role in creating the osmotic gradient that allows water to flow from blood plasma to CPE to CSF (CITE). Earlier theories have proposed a simple osmotic model in which NKCC1 is coupled to an aquaporin, so while NKCC1 moves sodium, potassium, and chloride into the CSF, water can follow via the coupled aquaporin. However, as Steffensen’s study asserts, this aquaporin-centric model of osmotic water transport is not sufficient to explain the normal rates of CSF production, noting among other points prior work that reveals only a 20% decline in CSF production after aquaporin-1 knockout in mice (CITE). Instead, Steffensen proposes a model in which water accompanies the flow of ions directly through NKCC1 as opposed through a coupled aquaporin. More work needs to be done to verify this proposal.
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