Liu CC, Zhao N, Yamaguchi Y, Cirrito JR, Kanekiyo T, Holtzman DM, Bu G. Neuronal heparan sulfates promote amyloid pathology by modulating brain amyloid-β clearance and aggregation in Alzheimer's disease. Sci Transl Med. 2016 Mar 30;8(332):332ra44. PubMed.

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  1. This is an excellent study showing that reduced neuronal HSPG biosynthesis in APP/PS1 transgenic mice results in less parenchymal amyloid deposition, but more cerebral amyloid angiopathy (CAA). A conditional knockout of the glycosyltransferase EXT1 in postmitotic neurons in the forebrains of APP/PS1 mice was generated. For the future, a more complete characterization of this bitransgenic as well as our Hpa x APP model might give further insights into the molecular mechanisms which are involved. Interestingly, the findings now reported complement and extend our cross-breeding study, which was done as a joint collaboration with Professor Jin-Ping Li and colleagues at Uppsala University in Sweden. We found decreased plaque burden in the cerebral cortex, as well as a reduced CAA burden when the HSPG-degrading enzyme, heparanase, was overexpressed in a less neuronal-selective manner in APPswe mice (Jendresen et al., 2015). 

    In the animal model now introduced by Liu et al., HSPG in cerebral vasculature was presumably not much affected by the neuron-specific EXT1 knockout as compared with our study, in which heparanase was more ubiquitously overexpressed. In the present report, elegant microdialysis studies were also used to show that the half-life of both Aβ40 and Aβ42 was reduced in the bitransgenic mice. Together the findings point to, as suggested, the importance of the perivascular drainage pathway for Aβ clearance with HSPG affecting Aβ turnover both in the parenchyma and the vasculature and perhaps also across the blood brain barrier (Bakker et al., 2016). The authors showed reduced Aβ oligomer levels in the mouse crosses, arguing that HSPG also increases the aggregation of Aβ. Effects on both Aβ clearance and Aβ aggregation are not surprising. It has also been reported for other amyloid-associated components, e.g., Apolipoprotein E (Nilsson et al., 2004; Hashimoto et al., 2012; Castellano et al., 2011). 

    These findings suggest multiple pathogenic mechanisms that could be targeted for therapeutics. HSPG biology has been strangely disregarded, in spite of quite strong indirect evidence that it might modify Alzheimer’s disease pathogenesis. Presumably, the neglect relates to the failed clinical trial with tramiprosate, a case of a poorly evaluated drug candidate that entered advanced clinical trials (Karran and Hardy, 2014). Like the old saying goes, “Don’t throw the baby out with the bathwater!”

    References:

    Jendresen CB, Cui H, Zhang X, Vlodavsky I, Nilsson LN, Li JP. Overexpression of heparanase lowers the amyloid burden in amyloid-β precursor protein transgenic mice. J Biol Chem. 2015 Feb 20;290(8):5053-64. Epub 2014 Dec 29 PubMed.

    Bakker EN, Bacskai BJ, Arbel-Ornath M, Aldea R, Bedussi B, Morris AW, Weller RO, Carare RO. Lymphatic Clearance of the Brain: Perivascular, Paravascular and Significance for Neurodegenerative Diseases. Cell Mol Neurobiol. 2016 Mar;36(2):181-94. Epub 2016 Mar 18 PubMed.

    Nilsson LN, Arendash GW, Leighty RE, Costa DA, Low MA, Garcia MF, Cracciolo JR, Rojiani A, Wu X, Bales KR, Paul SM, Potter H. Cognitive impairment in PDAPP mice depends on ApoE and ACT-catalyzed amyloid formation. Neurobiol Aging. 2004 Oct;25(9):1153-67. PubMed.

    Hashimoto T, Serrano-Pozo A, Hori Y, Adams KW, Takeda S, Banerji AO, Mitani A, Joyner D, Thyssen DH, Bacskai BJ, Frosch MP, Spires-Jones TL, Finn MB, Holtzman DM, Hyman BT. Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid β peptide. J Neurosci. 2012 Oct 24;32(43):15181-92. PubMed.

    Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, Patterson BW, Fagan AM, Morris JC, Mawuenyega KG, Cruchaga C, Goate AM, Bales KR, Paul SM, Bateman RJ, Holtzman DM. Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci Transl Med. 2011 Jun 29;3(89):89ra57. PubMed.

    Karran E, Hardy J. A critique of the drug discovery and phase 3 clinical programs targeting the amyloid hypothesis for Alzheimer disease. Ann Neurol. 2014 Aug;76(2):185-205. Epub 2014 Jul 2 PubMed.

    View all comments by Charlotte Jendresen

  2. This is an important study for the field of neurodegeneration as it underlines the relevance of HSPGs in sporadic Alzheimer’s disease (AD). Liu and colleagues clearly demonstrate that the conditional knockout of the Ext1 enzyme in the HSPG synthesis pathway significantly reduces the cortical and hippocampal Aβ plaque burden as well as Aβ in soluble fractions. The paper provides solid evidence for several mechanisms underlying the decrease of Aβ plaque deposition in the knockout mice: The reduction of cerebral heparin sulfate (HS) enhanced the clearance of soluble Aβ from the interstitial fluid (ISF), without affecting Aβ processing or expression. Moreover, consistent with previous findings in the literature (Castillo et al., 1999), the decrease of neuronal HS resulted in a reduction of Aβ aggregation.

    The authors used microdialysis to assess Aβ metabolism in the ISF. Several possible clearance mechanisms are discussed, including enhanced perivascular drainage, increased degradation by ISF proteases, and decreased cellular Aβ uptake and subsequent lysosomal aggregation and seed formation. Further investigations will show if one or several of the discussed pathways enhanced Aβ clearance in this study. It will be critical to understand in detail the underlying molecular pathways for future therapeutic approaches. 

    It is remarkable that only some classes of HSPG are increased in AD brains while for other classes no differences could be found between normal and AD brain tissue. This indicates that a certain HSPG pattern within the brain is connected to AD pathology, suggesting that further investigations of potential mechanisms should focus on these HSPG classes in particular. Moreover, AD pathology is known to follow a stereotypical neuroanatomical pattern (Thal et al., 2002) and it is tempting to hypothesize that specific HSPG expression patterns in the brain might contribute to this process. The question about the chronological order of events, i.e., if the AD-related Aβ burden triggers increased HSPG expression or vice versa, remains open and would equally be interesting to address in future studies.

    We strongly agree with the authors that HSPG-mediated uptake and transcellular propagation is a relevant mechanism to consider in HSPG-related AD pathology. As previously demonstrated by several groups, HSPG not only mediates cellular Aβ uptake (Kanekiyo et al., 2012) but also the uptake of other amyloidogenic proteins involved in neurodegenerative disorders such as tau, α-synuclein, and prion protein (Holmes et al., 2013; Horonchik et al., 2005). Thus, repeating the current study in other mouse models of neurodegeneration, such as tauopathies and synucleinopathies, will be very informative. The conditional Ext1 knockout seems to be an excellent model for this purpose, since it avoids the absence of HSPG knockout in the early embryological stages, which we would predict to be toxic since HSPG plays a major role in embryological development (Poulain and Yost, 2015). However, because “prion-like” amyloids could potentially play a physiological role in transcellular information trafficking (Sanders et al., 2016), side effects from a complete Ext1 knockout in tau or α-synuclein models need to be monitored carefully.

    In summary, the study highlights the relevance of HSPG in AD pathology and underlines the need for future studies to dissect the HSPG pathway for the purpose of finding innovative therapeutic approaches for AD and other neurodegenerative disorders.

    References:

    Castillo GM, Lukito W, Wight TN, Snow AD. The sulfate moieties of glycosaminoglycans are critical for the enhancement of beta-amyloid protein fibril formation. J Neurochem. 1999 Apr;72(4):1681-7. PubMed.

    Thal DR, Rüb U, Orantes M, Braak H. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology. 2002 Jun 25;58(12):1791-800. PubMed.

    Kanekiyo T, Liu CC, Shinohara M, Li J, Bu G. LRP1 in brain vascular smooth muscle cells mediates local clearance of Alzheimer's amyloid-β. J Neurosci. 2012 Nov 14;32(46):16458-65. PubMed.

    Holmes BB, DeVos SL, Kfoury N, Li M, Jacks R, Yanamandra K, Ouidja MO, Brodsky FM, Marasa J, Bagchi DP, Kotzbauer PT, Miller TM, Papy-Garcia D, Diamond MI. Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):E3138-47. Epub 2013 Jul 29 PubMed.

    Horonchik L, Tzaban S, Ben-Zaken O, Yedidia Y, Rouvinski A, Papy-Garcia D, Barritault D, Vlodavsky I, Taraboulos A. Heparan sulfate is a cellular receptor for purified infectious prions. J Biol Chem. 2005 Apr 29;280(17):17062-7. Epub 2005 Jan 24 PubMed.

    Poulain FE, Yost HJ. Heparan sulfate proteoglycans: a sugar code for vertebrate development?. Development. 2015 Oct 15;142(20):3456-67. PubMed.

    Sanders DW, Kaufman SK, Holmes BB, Diamond MI. Prions and Protein Assemblies that Convey Biological Information in Health and Disease. Neuron. 2016 Feb 3;89(3):433-48. PubMed.

    View all comments by Marc Diamond

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