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Importance of CSF-based Aβ clearance with age in humans increases with declining efficacy of blood-brain barrier/proteolytic pathways.

ABSTRACT: The kinetics of amyloid beta turnover within human brain is still poorly understood. We previously found a dramatic decline in the turnover of Aβ peptides in normal aging. It was not known if brain interstitial fluid/cerebrospinal fluid (ISF/CSF) fluid exchange, CSF turnover, blood-brain barrier function or proteolysis were affected by aging or the presence of β amyloid plaques. Here, we describe a non-steady state physiological model developed to decouple CSF fluid transport from other processes. Kinetic parameters were estimated using: (1) MRI-derived brain volumes, (2) stable isotope labeling kinetics (SILK) of amyloid-β peptide (Aβ), and (3) lumbar CSF Aβ concentration during SILK. Here we show that changes in blood-brain barrier transport and/or proteolysis were largely responsible for the age-related decline in Aβ turnover rates. CSF-based clearance declined modestly in normal aging but became increasingly important due to the slowing of other processes. The magnitude of CSF-based clearance was also lower than that due to blood-brain barrier function plus proteolysis. These results suggest important roles for blood-brain barrier transport and proteolytic degradation of Aβ in the development Alzheimer's Disease in humans.

SUBMITTER: Elbert DL

PROVIDER: S-EPMC8795390 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Importance of CSF-based Aβ clearance with age in humans increases with declining efficacy of blood-brain barrier/proteolytic pathways.

Elbert Donald L DL Patterson Bruce W BW Lucey Brendan P BP Benzinger Tammie L S TLS Bateman Randall J RJ

Communications biology 20220127 1

The kinetics of amyloid beta turnover within human brain is still poorly understood. We previously found a dramatic decline in the turnover of Aβ peptides in normal aging. It was not known if brain interstitial fluid/cerebrospinal fluid (ISF/CSF) fluid exchange, CSF turnover, blood-brain barrier function or proteolysis were affected by aging or the presence of β amyloid plaques. Here, we describe a non-steady state physiological model developed to decouple CSF fluid transport from other processe ...[more]

PMID: 35087179

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Project description:BACKGROUND:Infusion testing is a common procedure to determine whether shunting will be beneficial in patients with normal pressure hydrocephalus. The method has a well-developed theoretical foundation and corresponding mathematical models that describe the CSF circulation from the choroid plexus to the arachnoid granulations. Here, we investigate to what extent the proposed glymphatic or paravascular pathway (or similar pathways) modifies the results of the traditional mathematical models. METHODS:We used a compartment model to estimate pressure in the subarachnoid space and the paravascular spaces. For the arachnoid granulations, the cribriform plate and the glymphatic circulation, resistances were calculated and used to estimate pressure and flow before and during an infusion test. Finally, different variations to the model were tested to evaluate the sensitivity of selected parameters. RESULTS:At baseline intracranial pressure (ICP), we found a very small paravascular flow directed into the subarachnoid space, while 60% of the fluid left through the arachnoid granulations and 40% left through the cribriform plate. However, during the infusion, 80% of the fluid left through the arachnoid granulations, 20% through the cribriform plate and flow in the PVS was stagnant. Resistance through the glymphatic system was computed to be 2.73 mmHg/(mL/min), considerably lower than other fluid pathways, giving non-realistic ICP during infusion if combined with a lymphatic drainage route. CONCLUSIONS:The relative distribution of CSF flow to different clearance pathways depends on ICP, with the arachnoid granulations as the main contributor to outflow. As such, ICP increase is an important factor that should be addressed when determining the pathways of injected substances in the subarachnoid space. Our results suggest that the glymphatic resistance is too high to allow for pressure driven flow by arterial pulsations and at the same time too small to allow for a direct drainage route from PVS to cervical lymphatics.

Project description:BackgroundThe choroid plexus (CP) has been recently implicated in the pathogenesis of the neuropsychiatric manifestations of systemic lupus erythematosus (NPSLE). Lupus patients demonstrate increased serum and cerebrospinal fluid (CSF) concentrations of interleukin-6 (IL-6), which can disrupt vital blood-CSF barrier (B-CSFB) functions performed by the CP. However, difficulty accessing this tissue has largely precluded dynamic imaging or evaluation of CP barrier function in vivo.MethodsIn this study, explant CP spheroids which replicate the functional and structural properties of the B-CSFB were generated from 12 + week old female MRL/lpr (IL-6 wildtype; IL-6 WT) lupus mice, IL-6 knockout (IL-6 KO) MRL/lpr mice, and congenic control MRL/mpj mice. CP spheroids derived from IL-6 WT MRL/lpr mice were found to synthesize and secrete IL-6, similar to the CP in vivo, whereas the IL-6 KO spheroids did not produce IL-6. Accumulation of different fluorescent tracers within the central CSF-like fluid vacuole of spheroids, modeling brain ventricles, was measured to probe transcellular permeability, paracellular diffusion, and clearance functions of the CP.ResultsAs shown by blocking the IL-6 receptor in IL-6 WT spheroids or comparing them to IL-6 KO spheroids, IL-6 signaling decreased spheroid clearance of methotrexate, a chemotherapeutic drug employed in the therapy of lupus, and lucifer yellow. This suppression occurred without altering CP epithelial morphology and ultrastructure. Methotrexate and lucifer yellow efflux can occur through ATP-binding cassette (ABC) transporters, including BCRP and MRP1. Cytoplasmic accumulation of the ABC-specific dye fluorescein diacetate was also increased by IL-6. Pharmacologic inhibition of either BCRP or MRP1 in IL-6 KO spheroids was sufficient to recreate the clearance deficits observed in IL-6 WT spheroids. Moreover, CP expression of BCRP was significantly lower in IL-6 WT mice.ConclusionsIn this study, we establish, validate, and apply a CP spheroid model to the study of B-CSFB function in lupus. Our results show that IL-6, a key cytokine increased in NPSLE, can potentially suppress the CP-specific function and expression of BCRP and MRP1. Therefore, IL-6 could affect the CSF clearance of inflammatory substrates (e.g., leukotrienes), the accumulation of which would incite neurotoxicity and promote progression of NPSLE.

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Dataset Information

Importance of CSF-based Aβ clearance with age in humans increases with declining efficacy of blood-brain barrier/proteolytic pathways.

Publications

Importance of CSF-based Aβ clearance with age in humans increases with declining efficacy of blood-brain barrier/proteolytic pathways.

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