Keaney J, Walsh DM, O'Malley T, Hudson N, Crosbie DE, Loftus T, Sheehan F, McDaid J, Humphries MM, Callanan JJ, Brett FM, Farrell MA, Humphries P, Campbell M. Autoregulated paracellular clearance of amyloid-β across the blood-brain barrier. Sci Adv. 2015 Sep 4;1(8):e1500472. PubMed.

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  1. The brain’s microenvironment is strictly maintained by specialized highly vascularized barriers, including the blood-brain barrier (BBB) in the brain parenchyma and the blood-cerebrospinal fluid barrier (BCSFB) in the choroid plexus. Brkic et al. present an interesting study to evaluate the impact of synthetic human Aβ1-42 oligomers on BCSFB integrity in mice. The BCSFB, unique from the BBB due to its epithelial monolayer and fenestrated endothelium, contributes to central nervous system homeostasis by producing cerebrospinal fluid (CSF) and restricting the passage of undesirable molecules and pathogens into the brain, as well as by clearing metabolic waste products from CSF.

    This study found that Aβ1-42 injected mice have increased metalloproteinase (MMP) enzymatic activity and increased mRNA levels of MMP-3, in addition to morphological changes of choroid plexus epithelial cells and increased BCSFB permeability. These findings suggest that Aβ1-42 oligomers detrimentally impact BCSFB integrity, which can cause subsequent disruption of homeostasis of the neuronal internal milieu. Such disruption may also alter CSF production and impair Aβ clearance from the brain via the interstitial fluid (ISF)-CSF route.

    This study further reports that disrupted BCSFB permeability in response to Aβ1-42 oligomers can be reversed by the administration of a general MMP inhibitor as well as in Mmp3-/- mice. Overall, the present study is novel in shedding light on the negative impact of Aβ1-42 oligomers at the BCSFB and the potential ability of MMPs, specifically MMP-3, to mediate this effect. MMPs appear to be crucially important in regulating the integrity of the brain’s specialized vascular barriers, including both blood-brain barrier and blood-CSF barrier. At the BBB, for example, ApoE4 induces upregulation of MMP-9 in brain capillary pericytes that promotes BBB breakdown (Bell et al., 2012). The extent to which pericyte injuries can contribute to changes in BCSFB permeability remains, however, elusive at present, as well as the source of elevated MMP-3 activity, which all could present interesting directions for future studies.

    References:

    Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, Holtzman DM, Betsholtz C, Armulik A, Sallstrom J, Berk BC, Zlokovic BV. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature. 2012 May 24;485(7399):512-6. PubMed. Correction.

    View all comments by Berislav Zlokovic

  2. Impaired clearance of Aβ is a key contributing factor to Aβ accumulation in the brain and the progression of AD. Studies focusing on Aβ clearance mechanisms, regulation of Aβ efflux, and ways to modulate Aβ removal are of importance to the field. The blood-brain barrier, comprised of a tight monolayer of cerebral endothelial cells, authorizes molecules to enter and leave the brain. Keaney et al. present an interesting study using a systemic siRNA approach to manipulate expression of tight-junction proteins at the site of the blood-brain barrier, and determine how this affects the blood-brain barrier molecular permeability.

    The authors hypothesize that a controlled opening of the blood-brain barrier by downregulation of tight junction proteins—claudin-5 and occludin—permits a paracellular clearance of Aβ across the blood-brain barrier. They suggest a method for size-selective removal of Aβ facilitated by RNAi-mediated co-suppression of the two transmembrane tight-junction proteins. Opening the blood-brain barrier “on demand” is a difficult task, and if achieved successfully might aid in both the delivery of neuropharmaceuticals to the brain that otherwise cannot cross the blood-brain barrier and/or enhance clearance of potentially toxic products from the brain that contribute to brain pathology. However, the concept of “autoregulation”—a phenomenon where the brain itself enables paracellular clearance of Aβ during AD pathology—will need to be examined carefully and in relation to other multiple Aβ clearance mechanisms that exist physiologically. These mechanisms include the transvascular clearance across the blood-brain barrier, interstitial fluid bulk flow, i.e., traditional perivascular clearance, glymphatic paravascular clearance, cerebrospinal fluid absorption, and enzymatic degradation (Ramanathan et al., 2015). 

    The authors suggest that they can open the blood-brain barrier in a size-specific manner and, for example, allow only small molecules that are less than 10 kDa to pass. Future studies should proceed with caution because opening the blood-brain barrier may facilitate the entry of toxic blood-derived products, pathogens, and blood cells into the brain that have been shown to contribute to pathogenesis and neurodegenerative changes in monogenic rare human diseases, and may also influence the disease process in complex neurological diseases such as Alzheimer’s disease and amyotrophic lateral sclerosis. 

    References:

    Ramanathan A, Nelson AR, Sagare AP, Zlokovic BV. Impaired vascular-mediated clearance of brain amyloid beta in Alzheimer's disease: the role, regulation and restoration of LRP1. Front Aging Neurosci. 2015;7:136. Epub 2015 Jul 15 PubMed.

    View all comments by Berislav Zlokovic

  3. Both these very interesting studies (Keaney et al., 2015, and Brkic et al., 2015) build on our discovery that the blood-brain barrier is perturbed concomitantly with the initiation of new cerebral vessels in AD. During angiogenesis, which entails endothelial cell division, the tight junctions that mediate the barrier between the endothelial cells in the BBB are programmed to reorganize, barrier function is reduced, and permeability increased. It appears that amyloid(s) is the trigger for the angiogenesis we observe in both mice and humans with AD.

    Similar to Keaney et al., our earlier studies interpreted the BBB’s age-dependent breakdown and its increased permeability as being an impairment that allows the diffusion of proteins through the barrier (Ujiie et al., 2003; Dickstein et al., 2006). 

    However, that breakdown and permeability increase now appears to be a result of endothelial cell division rather than cellular deterioration (Biron et al., 2011; Biron et al., 2013).

    We also observed BBB angiogenesis in postmortem tissues from several pathology-confirmed cases of AD. Thus, these studies likely explain the mechanism that underpins the observations in Keaney et al.

    We and others interpret this brain endothelial cell division as being driven by amyloid(s). Elegant studies in zebrafish confirm this (Cameron et al., 2012). 

    Comparing the two recently published studies, one group studied brain endothelium (Keaney et al., 2015), the other epithelial cells in the choroid plexus (Brkic et al., 2015). These are different cell types, though it is perhaps interesting to ponder that amyloids appear to be triggering cell division rather than deterioration of either barrier. 

    References:

    Ujiie M, Dickstein DL, Carlow DA, Jefferies WA. Blood-brain barrier permeability precedes senile plaque formation in an Alzheimer disease model. Microcirculation. 2003 Dec;10(6):463-70. PubMed.

    Dickstein DL, Biron KE, Ujiie M, Pfeifer CG, Jeffries AR, Jefferies WA. Abeta peptide immunization restores blood-brain barrier integrity in Alzheimer disease. FASEB J. 2006 Mar;20(3):426-33. PubMed.

    Biron KE, Dickstein DL, Gopaul R, Jefferies WA. Amyloid triggers extensive cerebral angiogenesis causing blood brain barrier permeability and hypervascularity in Alzheimer's disease. PLoS One. 2011;6(8):e23789. PubMed.

    Biron KE, Dickstein DL, Gopaul R, Fenninger F, Jefferies WA. Cessation of neoangiogenesis in Alzheimer's disease follows amyloid-beta immunization. Sci Rep. 2013;3:1354. PubMed.

    Cameron DJ, Galvin C, Alkam T, Sidhu H, Ellison J, Luna S, Ethell DW. Alzheimer's-related peptide amyloid-β plays a conserved role in angiogenesis. PLoS One. 2012;7(7):e39598. PubMed.

    View all comments by Dara Dickstein

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