. Lack of Widespread BBB Disruption in Alzheimer's Disease Models: Focus on Therapeutic Antibodies. Neuron. 2015 Oct 21;88(2):289-97. PubMed.

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  1. This paper provides a comprehensive and quantitative assessment of the permeability of the blood-brain barrier in models of neurodegenerative diseases. Strengths of the assessment include the use of multiple mouse models of neurodegenerative diseases and ApoE status, use of quantitative and sensitive methods to assess transfer from the blood to the brain, use of BBB tracers of different sizes, and positive controls to demonstrate the sensitivity of the methods for detecting a breach in the BBB. While the studies do not support earlier observations suggesting a widespread “opening" of the BBB, they strengthen the rationale for developing approaches to promote the transfer of drug across the BBB for therapeutic purposes in neurodegenerative diseases.

    It remains unclear why the findings contradict previous observations of BBB disruption in neurodegenerative diseases. However, several considerations are in order. First, there have been few well-controlled studies examining permeability in neurodegenerative diseases. Second, existing studies have used different experimental conditions (anesthesia, cardiorespiratory status affecting the cerebral circulation, etc.) that could affect the BBB, which is more dynamic than previously believed. Third, the histological approaches most commonly used in postmortem BBB assessment were, for the most part, indirect and not quantitative and, as such, subject to false positive readings. 

    A well-tested way to resolve the discrepancy is for the investigators who reported conflicting results to perform experiments in each other’s laboratories under identical experimental conditions. Considering the impact of the BBB status in drug delivery to the brain, this is an important issue that would be worth resolving. 

    Irrespective of whether or not the BBB is open in advanced disease (as examined in the present paper), a key question concerns the status of the BBB in the presymptomatic phase of the disease process, because that would be the time to intervene in diseases like AD in which the pathogenic process precedes symptoms by decades.

    View all comments by Costantino Iadecola
  2. It is comforting to see that Bien-Ly and colleagues report on the absence of widespread BBB disruption in AD mouse models and that they further find that the levels of brain infarcts are similar in AD cases and healthy controls.

    We have recently become interested in transiently opening the BBB to clear amyloid from the brain of amyloid-depositing APP23 mice and restore memory functions using ultrasound (Leinenga et al., 2015).

    An argument one often encounters when discussing the potential application of ultrasound for transient BBB opening (an area pioneered by Drs. Hynynen and Konofagou, refs: Choi et al., 2011; Hynynen et al, 2005) is that the BBB is compromised in AD. The notion that in neurological disease “the BBB is leaky” disguises the fact that the brain is not completely sealed off from the periphery. For example, steady-state central nervous system levels of a peripherally administered anti-Aβ monoclonal antibody are approximately 0.1 percent of the level found in the plasma. This indicates that an active exchange takes place between the blood and the brain even under physiological conditions, i.e., when the BBB is neither manipulated nor damaged (Levites et al., 2006). 

    Bien-Ly and colleagues find that there is no increased passage of antibodies in multiple AD mouse models. Interestingly, some studies even indicate that rather than being more open, the BBB in AD mouse models is even tighter. Studies in AD mouse models indicate that the uptake of therapeutic drugs is significantly reduced in 3xTg mice that present with both a tau and an Aβ pathology compared to that in age-matched non-transgenic controls (Mehta et al., 2013). 

    References:

    . Scanning ultrasound removes amyloid-β and restores memory in an Alzheimer's disease mouse model. Sci Transl Med. 2015 Mar 11;7(278):278ra33. PubMed.

    . Noninvasive and localized neuronal delivery using short ultrasonic pulses and microbubbles. Proc Natl Acad Sci U S A. 2011 Oct 4;108(40):16539-44. Epub 2011 Sep 19 PubMed.

    . Local and reversible blood-brain barrier disruption by noninvasive focused ultrasound at frequencies suitable for trans-skull sonications. Neuroimage. 2005 Jan 1;24(1):12-20. PubMed.

    . Insights into the mechanisms of action of anti-Abeta antibodies in Alzheimer's disease mouse models. FASEB J. 2006 Dec;20(14):2576-8. Epub 2006 Oct 26 PubMed.

    . Altered Brain Uptake of Therapeutics in a Triple Transgenic Mouse Model of Alzheimer's Disease. Pharm Res. 2013 Jun 22; PubMed.

    View all comments by Jürgen Götz
  3. If you weigh 50 kg, you have approximately 60 g of IgG in your blood. Yet, immunohistochemistry of your brain parenchyma using anti-human IgG would generate essentially no immunoreactivity, indicating that only little, if any, IgG crosses the blood-brain barrier.

    This notion, consistent with the data shown in the paper, gives a warning against the use of monovalent (as opposed to divalent) anti-Aβ therapeutic antibodies in the large-scale longitudinal prevention trials mainly going on in the United States. Behind the scientific scene, a number of pharmaceutical companies are making efforts to engineer their antibodies to make them more BBB-permeable. It is also important that the antibodies are administered intravenously in human cases, whereas the injection paradigm for the model mice is almost always intraperitoneal. This difference may explain the discrepancy in the efficacy of immunotherapy between model mice and humans.

    The prevention protocols for the trials may be modified in the near future. One question is “Are we going in the right direction?” because immunotherapy is expensive. Success of immunotherapy will obviously open up more opportunities for the other anti-Aβ medications that would cost society and individual people less.

    A small concern about this paper is the Tg mouse model of AD used, which overexpresses mutant APP and PS. Overexpression of membrane proteins containing 1 and 9 TM domains, respectively, could induce non-specific ER stress. Overexpression of APP and PS transgenes results in the destruction of at least two gene loci in the host animals and may in principle generate artificial phenotypes.

    It is surprising that none of the Tg mice, to my knowledge, have been sequenced for defects. APP interacts with kinesin via JIP-1, hence APP overexpression may perturb axonal transport, causing axonal sprouting. In addition, APP overexpression also results in overproduction of non-Aβ APP fragments. In particular, CTF-β, which does not accumulate much in human AD brain and is recognized by most anti-Aβ antibodies, is known to be more toxic than Aβ.

    Based on these concerns, I would suggest that the authors examine whether their main findings are the result of APP and PS overexpression and not innate disease processes. We are willing to provide free to academic scientists our model mice that overproduce Aβ42 without overexpressing APP or PS1 (Saito et al., 2014). Right now, more than 130 laboratories all over the world are using these mice. We estimate that approximately 60 percent of the phenotypes in conventional APP Tg mice are artifacts. I invite the authors and other scientists experimentally working on AD in transgenic mouse models to recognize this and take steps to correct the APP overexpression paradigm.

    References:

    . Single App knock-in mouse models of Alzheimer's disease. Nat Neurosci. 2014 May;17(5):661-3. Epub 2014 Apr 13 PubMed.

    View all comments by Takaomi Saido
  4. The property of a therapeutic agent being able to penetrate the BBB is generally regarded as a prerequisite for anti-AD agents. Recently we found that 40 percent of the Aβ in the brain is catabolized by the peripheral organs and tissues, in particular, in liver, kidney, gastrointestinal tract and skin (Xiang et al., 2015). This finding suggests that drugs that directly act on Aβ in the periphery would have a therapeutic significance even though they do not pass through BBB. Indeed, peripheral administration of a single chain antibody (scFv) to Aβ is as effective as intracranial administration of the scFv in reducing brain Aβ burden (Wang et al., 2009). Enhancement of Aβ degradation in liver by Withania somnifera extracts significantly reduced Aβ levels in the brain (Sehgal et al., 2012). Continuous peripheral expression of the NEP gene in skeletal muscle is able to reduce brain Aβ burden (Guan et al., 2009; Liu et al., 2009Liu et al., 2010). Thus drug development against Aβ in the future can focus on the clearance of Aβ from the circulation and might be a promising therapeutic approach for AD.

    References:

    . Peripherally expressed neprilysin reduces brain amyloid burden: a novel approach for treating Alzheimer's disease. J Neurosci Res. 2009 May 1;87(6):1462-73. PubMed.

    . Expression of neprilysin in skeletal muscle reduces amyloid burden in a transgenic mouse model of Alzheimer disease. Mol Ther. 2009 Aug;17(8):1381-6. PubMed.

    . Circulating neprilysin clears brain amyloid. Mol Cell Neurosci. 2010 Oct;45(2):101-7. PubMed.

    . Withania somnifera reverses Alzheimer's disease pathology by enhancing low-density lipoprotein receptor-related protein in liver. Proc Natl Acad Sci U S A. 2012 Feb 28;109(9):3510-5. Epub 2012 Jan 30 PubMed.

    . Intramuscular delivery of a single chain antibody gene reduces brain Abeta burden in a mouse model of Alzheimer's disease. Neurobiol Aging. 2009 Mar;30(3):364-76. PubMed.

    . Physiological amyloid-beta clearance in the periphery and its therapeutic potential for Alzheimer's disease. Acta Neuropathol. 2015 Oct;130(4):487-99. Epub 2015 Sep 12 PubMed.

    View all comments by Yan-Jiang Wang

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