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• W1796655907 abstract "Blood-brain barrier disruption is believed to occur in Alzheimer’s disease, which could influence the bioavailability of drugs within the brain. However, in this issue of Neuron, Bien-Ly et al., 2015Bien-Ly N. Boswell C.A. Jeet S. Beach T.G. Hoyte K. Luk W. Shihadeh V. Ulufatu S. Foreman O. Lu Y. et al.Neuron. 2015; 88 (this issue): 289-297Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar report no evidence of widespread blood-brain barrier dysfunction. Blood-brain barrier disruption is believed to occur in Alzheimer’s disease, which could influence the bioavailability of drugs within the brain. However, in this issue of Neuron, Bien-Ly et al., 2015Bien-Ly N. Boswell C.A. Jeet S. Beach T.G. Hoyte K. Luk W. Shihadeh V. Ulufatu S. Foreman O. Lu Y. et al.Neuron. 2015; 88 (this issue): 289-297Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar report no evidence of widespread blood-brain barrier dysfunction. Alzheimer’s disease (AD) is the most common cause of dementia, affecting over 5 million individuals in the United States. As the population ages, the impact of AD is expected to become even more severe, with the number of cases of AD expected to triple by 2050. Cross-sectional and longitudinal studies indicate that the pathological process of AD begins with the deposition of amyloid-β (Aβ) plaques in the brain ∼10–20 years prior to the onset of cognitive impairment (Jack and Holtzman, 2013Jack Jr., C.R. Holtzman D.M. Neuron. 2013; 80: 1347-1358Abstract Full Text Full Text PDF PubMed Scopus (610) Google Scholar). Subsequent to the appearance of Aβ plaques is the progressive appearance of tau-containing neurofibrillary tangles in the neocortex along with neuronal death and the manifestation of clinical dementia (Jack and Holtzman, 2013Jack Jr., C.R. Holtzman D.M. Neuron. 2013; 80: 1347-1358Abstract Full Text Full Text PDF PubMed Scopus (610) Google Scholar). Currently there are no effective treatments to cure, prevent, or slow the progression of AD. Efforts at developing a therapy for AD have largely focused on reducing amyloid or tau pathology through small molecule inhibitors of Aβ production or immunotherapy approaches targeting Aβ or, more recently, tau (Wisniewski and Goñi, 2015Wisniewski T. Goñi F. Neuron. 2015; 85: 1162-1176Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar). Drug development for diseases of the central nervous system (CNS) has always been particularly challenging due to the restriction of the brain bioavailability of therapeutics by the blood-brain barrier (BBB), the specialized network of endothelial cells, astrocytes, and pericytes that restricts the entry of blood-borne molecules into the CNS (Figure 1A) (Daneman and Prat, 2015Daneman R. Prat A. Cold Spring Harb. Perspect. Biol. 2015; 7: a020412Crossref Scopus (1370) Google Scholar). In the case of passive immunotherapy with monoclonal antibodies, an intact BBB restricts all but approximately 0.1%–0.2% of peripherally administered antibody from entering the brain, meaning otherwise promising therapy strategies may fail in the clinic due to insufficient entry of the antibody into the CNS with subsequent target engagement (Figure 1B). One promising approach to increase brain penetrance of therapeutic antibodies is to engineer them to be actively transported across the BBB using an endogenous transcytosis mechanism such as the transferrin receptor (TfR) (Watts and Dennis, 2013Watts R.J. Dennis M.S. Curr. Opin. Chem. Biol. 2013; 17: 393-399Crossref PubMed Scopus (65) Google Scholar). For example, previous studies found that bispecific anti-BACE1/TfR antibodies exhibited a pronounced increase in brain uptake relative to anti-BACE1 antibodies (Yu et al., 2014Yu Y.J. Atwal J.K. Zhang Y. Tong R.K. Wildsmith K.R. Tan C. Bien-Ly N. Hersom M. Maloney J.A. Meilandt W.J. et al.Sci. Transl. Med. 2014; 6: 261ra154Crossref PubMed Scopus (231) Google Scholar). However, to what degree the BBB remains intact and an impediment to CNS drug delivery in the context of neurodegenerative disease is unclear. Neurovascular lesions are observed in multiple sclerosis (MS) and AD patients, and mouse models of neurodegenerative diseases, such as the experimental allergic encephalomyelitis (EAE) model of MS, exhibit BBB breakdown (Zlokovic, 2011Zlokovic B.V. Nat. Rev. Neurosci. 2011; 12: 723-738Crossref PubMed Scopus (1803) Google Scholar). On the one hand, the resulting accumulation of neurotoxic peripheral proteins and microbleeds could augment neurodegeneration in AD; on the other hand, a disrupted BBB could also allow for greater brain bioavailability of therapeutics, which would obviate the need for modification strategies to circumvent the BBB. In this edition of Neuron, Bien-Ly et al., 2015Bien-Ly N. Boswell C.A. Jeet S. Beach T.G. Hoyte K. Luk W. Shihadeh V. Ulufatu S. Foreman O. Lu Y. et al.Neuron. 2015; 88 (this issue): 289-297Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar assessed whether there were global disruptions in the BBB in mouse models of AD that were sufficient to alter the ability of antibodies to enter the CNS. The authors employed a variety of neurodegenerative disease models and a set of highly quantitative and sensitive ELISAs and radiolabeled tracer methodologies to measure the degree of passive diffusion through the BBB with a particular focus on the brain uptake of monoclonal antibodies. The authors elected to compare the degree of passive antibody diffusion in the context of various neurodegenerative environments against the bispecific anti-BACE1/TfR antibody, which, as described previously, consistently displayed greater brain uptake than anti-BACE1 or a control IgG antibody (Yu et al., 2014Yu Y.J. Atwal J.K. Zhang Y. Tong R.K. Wildsmith K.R. Tan C. Bien-Ly N. Hersom M. Maloney J.A. Meilandt W.J. et al.Sci. Transl. Med. 2014; 6: 261ra154Crossref PubMed Scopus (231) Google Scholar). In inflammatory conditions known to cause massive disruption of the BBB, such as the EAE model of MS or following LPS injection, there was a pronounced increase in the level of antibody and radiotracers detected in the brain following peripheral administration (Figure 1C). However, Bien-Ly et al., 2015Bien-Ly N. Boswell C.A. Jeet S. Beach T.G. Hoyte K. Luk W. Shihadeh V. Ulufatu S. Foreman O. Lu Y. et al.Neuron. 2015; 88 (this issue): 289-297Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar found that there was no difference between normal mice and mouse models with AD pathology in regard to the levels of antibody or radiotracers entering the brain (Figure 1D). Consistent with these findings, the levels of the plasma protein albumin in the CNS were elevated in the EAE mode, but not in the models with AD pathology. Overall, the authors conclude these results argue that the BBB remains largely intact in the context of Aβ deposition or tauopathy, meaning that strategies to increase CNS delivery of AD therapeutics remains an important area of study. One significant contributor to BBB pathology in AD is the presence of cerebral amyloid angiopathy (CAA), a vascular disease that results from the deposition of fibrillar Aβ in cerebral arterial and capillary vessel walls (Zlokovic, 2011Zlokovic B.V. Nat. Rev. Neurosci. 2011; 12: 723-738Crossref PubMed Scopus (1803) Google Scholar). The presence of these vascular Aβ deposits can cause vascular smooth muscle dysfunction leading to reduced regional cerebral blood flow and hemorrhaging. In addition to CAA, though, previous studies have suggested that soluble Aβ species can also affect vascular function and that BBB dysfunction can precede plaque deposition in mouse models (Biron et al., 2011Biron K.E. Dickstein D.L. Gopaul R. Jefferies W.A. PLoS ONE. 2011; 6: e23789Crossref PubMed Scopus (215) Google Scholar, Han et al., 2008Han B.H. Zhou M.L. Abousaleh F. Brendza R.P. Dietrich H.H. Koenigsknecht-Talboo J. Cirrito J.R. Milner E. Holtzman D.M. Zipfel G.J. J. Neurosci. 2008; 28: 13542-13550Crossref PubMed Scopus (113) Google Scholar). However, Bien-Ly et al., 2015Bien-Ly N. Boswell C.A. Jeet S. Beach T.G. Hoyte K. Luk W. Shihadeh V. Ulufatu S. Foreman O. Lu Y. et al.Neuron. 2015; 88 (this issue): 289-297Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar observed no evidence of widespread BBB permeability in either young PS2-APP mice with very little plaque deposition or in old PS2-APP mice with more extensive plaque deposition. As noted by Bien-Ly et al., PS2-APP mice exhibit predominantly parenchymal rather than vascular fibrillar Aβ deposition, which may affect the degree to which Aβ pathology would influence BBB permeability. Thus, it would be interesting to apply the highly quantitative methods employed in this study to determine if the presence of more extensive CAA affected the passive diffusion of IgG into the brain (Figure 1E). In addition to assessing the integrity of the BBB in neurodegenerative disease models, Bien-Ly et al., 2015Bien-Ly N. Boswell C.A. Jeet S. Beach T.G. Hoyte K. Luk W. Shihadeh V. Ulufatu S. Foreman O. Lu Y. et al.Neuron. 2015; 88 (this issue): 289-297Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar also examined whether the presence of apoE4 altered BBB permeability to IgG. The APOEε4 allele is the strongest known genetic risk factor for developing late-onset AD and also is associated with a greater incidence of CAA. Furthermore, APOEε4 carriers have previously been reported to exhibit changes in activity-dependent regional cerebral blood flow without evidence of AD pathology. Several studies suggest that apoE4 is deleterious to BBB function in vitro and in vivo. A previous study using demonstrated increased BBB leakage using in vivo microscopy of fluorescent tracers in young mice expressing apoE4 and in apoE−/− mice (Bell et al., 2012Bell R.D. Winkler E.A. Singh I. Sagare A.P. Deane R. Wu Z. Holtzman D.M. Betsholtz C. Armulik A. Sallstrom J. et al.Nature. 2012; 485: 512-516Crossref PubMed Google Scholar). The increased BBB permeability observed in these mice was associated with a decrease in apoE-dependent pericyte-expressed LRP1 activation and a concomitant increase in CypA-MMP9 activity (Bell et al., 2012Bell R.D. Winkler E.A. Singh I. Sagare A.P. Deane R. Wu Z. Holtzman D.M. Betsholtz C. Armulik A. Sallstrom J. et al.Nature. 2012; 485: 512-516Crossref PubMed Google Scholar). A subsequent study found increased pericyte degeneration and extravasation of IgG in AD patients who were APOEε4 carriers compared to those who were APOEε3 carriers (Halliday et al., 2015Halliday M.R. Rege S.V. Ma Q. Zhao Z. Miller C.A. Winkler E.A. Zlokovic B.V. J. Cereb. Blood Flow Metab. 2015; https://doi.org/10.1038/jcbfm.2015.44Crossref PubMed Scopus (346) Google Scholar). Interestingly, pericyte degeneration in these subjects was correlated with elevated levels of CypA and MMP9, similar to what was observed in mice expressing apoE4 (Halliday et al., 2015Halliday M.R. Rege S.V. Ma Q. Zhao Z. Miller C.A. Winkler E.A. Zlokovic B.V. J. Cereb. Blood Flow Metab. 2015; https://doi.org/10.1038/jcbfm.2015.44Crossref PubMed Scopus (346) Google Scholar). However, Bien-Ly et al. observed no difference in apoE4 or apoE−/− mice in the level of brain IgG uptake or in the level of radiotracer uptake in apoE−/− mice. This finding is in agreement with a recent report that also found no difference in the brain uptake of IgG or [14C]-sucrose in mice expressing apoE2, E3, or E4 (Alata et al., 2015Alata W. Ye Y. St-Amour I. Vandal M. Calon F. J. Cereb. Blood Flow Metab. 2015; 35: 86-94Crossref PubMed Scopus (104) Google Scholar). The aggregate of these results may suggest that, though there may be highly localized apoE4-dependent disruptions in BBB integrity, these localized disruptions do not alter the global homeostatic capacity of the BBB. Determining the brain bioavailability of IgG used in passive immunotherapy for AD is critically important, especially for antibodies that target Aβ or tau. Several trials of Aβ immunotherapies have revealed a still poorly understood phenomenon observed in MRI scans known as amyloid-related imaging abnormality (ARIA) (Sperling et al., 2011Sperling R.A. Jack Jr., C.R. Black S.E. Frosch M.P. Greenberg S.M. Hyman B.T. Scheltens P. Carrillo M.C. Thies W. Bednar M.M. et al.Alzheimers Dement. 2011; 7: 367-385Abstract Full Text Full Text PDF PubMed Scopus (408) Google Scholar). ARIA can be associated with microhemorrhages or vasogenic edema, possibly as a result of an Aβ clearance process or inflammation (Sperling et al., 2011Sperling R.A. Jack Jr., C.R. Black S.E. Frosch M.P. Greenberg S.M. Hyman B.T. Scheltens P. Carrillo M.C. Thies W. Bednar M.M. et al.Alzheimers Dement. 2011; 7: 367-385Abstract Full Text Full Text PDF PubMed Scopus (408) Google Scholar). Although the mechanistic basis for ARIA is unclear, the risk of ARIA is increased in APOEε4 carriers and is positively correlated with the presence of CAA (Sperling et al., 2011Sperling R.A. Jack Jr., C.R. Black S.E. Frosch M.P. Greenberg S.M. Hyman B.T. Scheltens P. Carrillo M.C. Thies W. Bednar M.M. et al.Alzheimers Dement. 2011; 7: 367-385Abstract Full Text Full Text PDF PubMed Scopus (408) Google Scholar). In addition, higher dosing of Aβ immunotherapy may increase the risk of ARIA. Although Bien-Ly et al., 2015Bien-Ly N. Boswell C.A. Jeet S. Beach T.G. Hoyte K. Luk W. Shihadeh V. Ulufatu S. Foreman O. Lu Y. et al.Neuron. 2015; 88 (this issue): 289-297Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar did not observe a change in IgG brain bioavailability following a single administration, it would be worthwhile to test whether chronic dosing of an IgG, particularly one targeting fibrillar Aβ, could alter the permeability of the BBB. The allure of antibody therapy as a “magic bullet” for human disease continues to inspire passive immunotherapy research. Given promising preclinical data that passive immunotherapy against Aβ and tau alleviates neurodegenerative phenotypes in mouse models, AD would seem to be a target-rich environment. The findings of a robust BBB presented by Bien-Ly et al., 2015Bien-Ly N. Boswell C.A. Jeet S. Beach T.G. Hoyte K. Luk W. Shihadeh V. Ulufatu S. Foreman O. Lu Y. et al.Neuron. 2015; 88 (this issue): 289-297Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar would indicate that methodologies to increase the bioavailability of therapeutic antibodies will continue to be an important facet of AD immunotherapy efforts. D.M.H. is a co-founder and on the scientific advisory booard of C2N Diagnostics, LLC. C2N has licensed intellectual property from Washington University on the therapeutic use of anti-tau antibodies. This intellectual property has licensed by C2N to AbbVie. D.M.H. is on the scientific advisory board of Genentech, Neurophage, and AstraZeneca and consults for Eli Lilly and AbbVie. Lack of Widespread BBB Disruption in Alzheimer’s Disease Models: Focus on Therapeutic AntibodiesBien-Ly et al.NeuronOctober 21, 2015In BriefIt is generally believed that neurodegeneration is accompanied by BBB dysfunction, potentially increasing drug bioavailability in the CNS. Bien-Ly et al. report that AD mouse models lack widespread BBB disruption and display restricted passive permeability to therapeutic antibodies. Full-Text PDF Open Archive" @default.
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• W1796655907 title "Re-evaluation of the Blood-Brain Barrier in the Presence of Alzheimer’s Disease Pathology" @default.
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