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The general consensus that NKCC1 plays a role in CSF homeostasis becomes relevant, as our analysis of two GEO databases revealed a decrease in NKCC1 expression levels in AD versus control CP. This finding is in harmony with the general decrease in CSF production seen in late stage AD, but runs counter to earlier work that suggested an upregulation of sodium-potassium-chloride cotransporters in AD CP (CITE Johanson AD CSF ion paper). Given the proposed central role of NKCC1 in mediating osmotic flow for CSF production, downregulation of NKCC1 in AD CP lends credence to the hypothesis that downregulation of NKCC1 is a causal factor behind impaired CSF homeostasis seen in AD. This hypothesis, along with any potential cause and effect relationships, must be verified in a future experiment.
Discovering expression of NKCC2, a gene thought to be expressed only in kidneys, was an interesting finding while mining the GEO databases. Like NKCC1, NKCC2 displayed downregulation in AD, albeit not as significantly as NKCC1. In kidney, NKCC2 participates in salt reabsorption in the distal tubule, and unlike NKCC1, displays no evidence of the cotransport of water (CITE). It is possible that potential NKCC2 in the CP serves a similar role or a radically different role. Because no research has been conducted on this gene’s role in the CPE, we can say nothing about the specific impact of this downregulation on CP function and CSF production.
Genes for the potassium-chloride cotransporters (KCC) displayed diversity in their expression level changes in AD. We found upregulation of SLC12A7 (KCC4) and SLC12A6 (KCC3), along with downregulation of SLC12A4 (KCC1), in AD. Localization of the KCC4 protein to the apical membrane of mouse CP has been determined (CITE). KCC3 has been localized to the basolateral mouse CPE (CITE). Functional analysis of the KCC channels in CPE has yet to be conducted, although current theories propose that KCC3, capable of facilitating potassium efflux from basolateral CPE into the blood, may play an important role in the removal of potassium from the CSF (CITE Brown).
Upregulation of KCC3 in conjunction with the significant downregulation of NKCC1, the major pathway for potassium influx into the CSF, discussed earlier would suggest a considerable decrease in the potassium ion concentration in the CSF. A further consequence of a decrease in the potassium ion gradient in the CSF could be a decrease in chloride ion transport into the CSF due to the close coupling of sodium-potassium-chloride transport. However, other studies have reported that potassium ion concentrations in the CSF remain unchanged in AD, .which suggests that compensatory mechanisms for CSF ion homeostasis may be at play (CITE CP in AD from Johanson). Perhaps elucidation of the functional significance of additional KCC channels (e.g. those of KCC4 and KCC1 whose expression levels also changed in AD), along with other potassium ion transporters will provide answers to this problem.
Bicarbonate has proven to be a critical ion powering solute transport across the CPE (CITE). Many transporters utilize bicarbonate concentration gradients to facilitate the movement of other cations and anions either down or against their own concentration gradients into and out of the CPE. A secondary effect of bicarbonate-coupled transport is to help with regulation of pH of the CSF and brain extracellular fluid (CITE-Christensen). It is important to note here that the BBB is impermeable to bicarbonate and hydrogen ions, so pH homeostasis by bicarbonate must occur via the BCSFB interface. Indeed, a current model, based on experimental evidence that carbon dioxide stimulation increases CSF bicarbonate levels to compensate for increased acidity, along with a corresponding increase in CSF sodium concentrations, proposes that CPE regulates pH of CSF through secretion and absorption of acid-base equivalents in a sodium-dependent manner (CITE).
Several bicarbonate-cation/anion cotransporters are expressed in the CPE, and we discovered significant changes in gene expression in AD for three members of this SLC4 family: the sodium dependent chloride-bicarbonate exchanger SLC4A10, the sodium-bicarbonate cotransporter SLC4A5, and the chloride-bicarbonate exchanger SLC4A2. SLC4A10 has been localized to the basolateral CPE, where it mediates the influx of one sodium and one bicarbonate ion per efflux of one chloride (CITE Brown). Knockout studies of SLC4A10 in mice have shown an 80 percent decrease in brain ventricular volume, most likely a consequence of decreased CSF production due to knockout. Moreover, the same study revealed microvilli reduction and CPE intracellular space enlargement in SLC4A10 knockout mice. These results are in harmony with our GEO database results that displayed downregulation of SLC4A10 in AD CP given current knowledge concerning the decrease in CSF production that is a feature of AD.
Our search also revealed decreased expression of SLC4A5 and SLC4A2 in AD versus control CP. SLC4A5, expressed in the apical CPE, mediates the transport of three bicarbonate ions plus one sodium ion from the CPE into the CSF, a stoichiometric observation that lends evidence to the notion that it plays a central role in CSF pH regulation (CITE Christensen). Knockout of SLC4A5 in one mouse study revealed results similar to knockout of SLC4A10: decreased lateral ventricular volume, decreased intracranial pressure, and changes in CPE structure (CITE first KO). However, a second knockout mouse study utilizing a different knockout mechanism revealed hypertension and metabolic acidosis, but no changes in brain ventricular volume (CITE second KO). More work will need to be done to present a clearer picture of the role of SLC4A10 in CSF homeostasis, although decreased expression of this gene seems to be a good candidate to help explain the decrease in CSF production observed in AD.
With respect to SLC4A2, such chloride-bicarbonate exchangers play roles in intracellular pH regulation in a variety of cells (CITE Alper). Localization studies have placed SLC4A2 in the basolateral CPE, leading some to suggest that its main role in CPE is more in the domain of pH regulation than CSF production (CITE Lindsey). However, other studies have shown that inhibition of the chloride-bicarbonate exchanger leads to significant inhibition of chloride transport into the CSF. This led to a new hypothesis that the chloride-bicarbonate exchanger may be implicated in chloride influx from the blood plasma into the basolateral CPE, which in turn provides the apical CPE with the chloride needed for export into the CSF via other transport proteins (CITE Brown). Our results showcasing decreased expression of SLC4A2 in AD CP may provide support for this hypothesis given observations of decreased CSF production in AD.
Discussing the role of bicarbonate in CP function would be incomplete without examining the importance of the carbonic anhydrase gene family. Carbonic anhydrases catalyze the production of bicarbonate and hydrogen ions from water and carbon dioxide (CITE Brown). Distribution studies have located carbonic anhydrase genes in both the membrane and cytoplasm of CPE (CITE). Our interrogation of the GEO databases revealed significant diversity in expression level changes of carbonic anhydrase genes in AD. CA4, CA8, CA1, CA2, and CA3 were found to be downregulated in AD relative to control CP while CA13, CA7, CA5B, and CA11 were found to be upregulated in AD relative to control CP.
Work by Vogh confirmed that inhibitors of carbonic anhydrases reduce CSF production by well over 50 percent (CITE Vogh). This suggests that a sizeable portion of CSF production depends on the intracellular production of bicarbonate ions in CPE. Stated another way, import of bicarbonate alone (e.g. through the sodium-dependent bicarbonate transporter) likely does not provide sufficient amounts of the ion to facilitate CPE CSF secretory process that heavily depend on bicarbonate exchange, many of which were described earlier. Therefore, decreased expression of key carbonic anhydrase genes in AD could be factor underlying AD-related decreases in CSF production. Likewise, upregulation of certain carbonic anhydrase genes may be a compensatory mechanism for downregulation of other carbonic anhydrases reflecting the CP effort to preserve CSF homeostasis, albeit with futility. As with several genes in the CPE, the specific functions of individual carbonic anhydrase genes need to be determined, and only then can any verifiable conclusions be drawn as to the meaning of expression level changes of specific carbonic anhydrase genes in CP.
Returning to the solute carrier gene family, our search revealed expression level differences in AD for several transporters involved in intracellular energy production in CP. We observed downregulation of SLC38A3, a system N amino acid transporter, in AD. SLC38A3 has been found to be highly expressed in One key substrate of this transporter is glutamine, used by many cells as a precursor for ATP synthesis (CITE SLC expression profiling paper). Theories abound that SLC38A3 and other system N transporters in the CP act to remove glutamine from the CSF into the CPE. No knockout studies have been conducted to verity these hypotheses. Two other substrates of this transporter, histidine and asparagine, are also important for brain homeostasis.
Downregulation of SLC38A3 may help explain decreased CSF production in AD by providing a metabolic hypothesis to underpin altered CP function. Such a model would suggest that decreased ATP synthesis due to decreased glutamine import into CPE will decrease the activity of active solute transporters necessary to maintain homeostatic rates of CSF production. Furthermore, our search revealed upregulation of two genes of the SLC25 family in AD relative to control CP: SLC25A28 and SLC25A37, two mitochondrial iron transporters. Iron is imperative for formation of iron-sulfur complexes needed by mitochondrial enzymes that drive the citric acid cycle and oxidative phosphorylation reactions. Upregulation of SLC25A28 and SLC25A37 in AD may be indicative of altered mitochondrial activity or function in AD CPE, which in turn will affect cellular ATP levels.
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