Cruz Hernández JC, Bracko O, Kersbergen CJ, Muse V, Haft-Javaherian M, Berg M, Park L, Vinarcsik LK, Ivasyk I, Rivera DA, Kang Y, Cortes-Canteli M, Peyrounette M, Doyeux V, Smith A, Zhou J, Otte G, Beverly JD, Davenport E, Davit Y, Lin CP, Strickland S, Iadecola C, Lorthois S, Nishimura N, Schaffer CB. Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer's disease mouse models. Nat Neurosci. 2019 Mar;22(3):413-420. Epub 2019 Feb 11 PubMed.

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  1. With interest we have read the article of Hernández and colleagues investigating the underlying mechanism behind the observation of reduced cerebral blood flow in Alzheimer’s disease.

    Cerebral blood flow is an interesting measure by which to investigate the interaction between vascular dysregulation and AD. This study would suggest that there is a link between dysfunction of the vessels and the accumulation of amyloid in the brain, leading to cognitive impairment. 

    The role of reduced cerebral blood flow in Alzheimer’s disease is still poorly understood. Studies of the association between cerebral blood flow, measured with different modalities (e.g., arterial spin labeling, two-dimensional phase-contrast MRI, or transcranial Doppler), and cognitive function in memory-clinic and population-based studies, showed, in general, modest effect sizes (Leeuwis et al., 2018; Leeuwis et al., 2017; Poels et al., 2008). It would be interesting to investigate at which stage of disease the process of neutrophil plugging in the capillaries begins. Is the interaction of neutrophil in the vessels a terminal event in the pathophysiology of AD or is it an early driver of pathology and cognitive impairment? In addition, it would be interesting to investigate if the same mechanism is found in mouse models with reduced cerebral blood flow due to vascular dysregulation, for example in hypertensive mouse models or mouse models with occlusion of the carotid. Targeting the neutrophil adhesion may be beneficial, as suggested by the cognitive benefit observed in this study.

    References:

    Leeuwis AE, Smith LA, Melbourne A, Hughes AD, Richards M, Prins ND, Sokolska M, Atkinson D, Tillin T, Jäger HR, Chaturvedi N, van der Flier WM, Barkhof F. Cerebral Blood Flow and Cognitive Functioning in a Community-Based, Multi-Ethnic Cohort: The SABRE Study. Front Aging Neurosci. 2018;10:279. Epub 2018 Sep 18 PubMed.

    Leeuwis AE, Benedictus MR, Kuijer JP, Binnewijzend MA, Hooghiemstra AM, Verfaillie SC, Koene T, Scheltens P, Barkhof F, Prins ND, van der Flier WM. Lower cerebral blood flow is associated with impairment in multiple cognitive domains in Alzheimer's disease. Alzheimers Dement. 2017 May;13(5):531-540. Epub 2016 Sep 28 PubMed.

    Poels MM, Ikram MA, Vernooij MW, Krestin GP, Hofman A, Niessen WJ, van der Lugt A, Breteler MM. Total cerebral blood flow in relation to cognitive function: the Rotterdam Scan Study. J Cereb Blood Flow Metab. 2008 Oct;28(10):1652-5. Epub 2008 Jun 25 PubMed.

    View all comments by Annebet Leeuwis

  2. In this elegant study, the authors used in vivo two-photon excited fluorescence (2PEF) microscopy to demonstrate that in APP/PS1, 5xFAD, as well as TgCRND8 mice there is capillary stalling that does not change with advancement of Aβ plaque pathology or in awake vs. anaesthetized mice. The stalling is due to neutrophils and the authors demonstrate that antibodies against Ly6G reduced the stalling within 10 minutes and improved the cerebral blood flow as well as cognition. This is highly significant for future therapeutic targets in Alzheimer’s disease, as targeting the adhesion of leukocytes to the endothelium should be achievable and with potential for significantly improving the clinical picture at mild to moderate stages of the disease, before the walls of blood vessels become compromised (Sweeney et al., 2019). An improvement of cerebral blood flow will not only result in enhanced perfusion of the brain, but also more efficient vasomotion that will likely result in facilitating intramural periarterial drainage (Aldea et al., 2019; Morris et al., 2016). 

    References:

    Sweeney MD, Montagne A, Sagare AP, Nation DA, Schneider LS, Chui HC, Harrington MG, Pa J, Law M, Wang DJ, Jacobs RE, Doubal FN, Ramirez J, Black SE, Nedergaard M, Benveniste H, Dichgans M, Iadecola C, Love S, Bath PM, Markus HS, Salman RA, Allan SM, Quinn TJ, Kalaria RN, Werring DJ, Carare RO, Touyz RM, Williams SC, Moskowitz MA, Katusic ZS, Lutz SE, Lazarov O, Minshall RD, Rehman J, Davis TP, Wellington CL, González HM, Yuan C, Lockhart SN, Hughes TM, Chen CL, Sachdev P, O'Brien JT, Skoog I, Pantoni L, Gustafson DR, Biessels GJ, Wallin A, Smith EE, Mok V, Wong A, Passmore P, Barkof F, Muller M, Breteler MM, Román GC, Hamel E, Seshadri S, Gottesman RF, van Buchem MA, Arvanitakis Z, Schneider JA, Drewes LR, Hachinski V, Finch CE, Toga AW, Wardlaw JM, Zlokovic BV. Vascular dysfunction-The disregarded partner of Alzheimer's disease. Alzheimers Dement. 2019 Jan;15(1):158-167. PubMed. Correction.

    Aldea R, Weller RO, Wilcock DM, Carare RO, Richardson G. Cerebrovascular Smooth Muscle Cells as the Drivers of Intramural Periarterial Drainage of the Brain. Front Aging Neurosci. 2019;11:1. Epub 2019 Jan 23 PubMed.

    Morris AW, Sharp MM, Albargothy NJ, Fernandes R, Hawkes CA, Verma A, Weller RO, Carare RO. Vascular basement membranes as pathways for the passage of fluid into and out of the brain. Acta Neuropathol. 2016 May;131(5):725-36. Epub 2016 Mar 14 PubMed.

    View all comments by Roxana Carare

  3. This is an excellent study providing evidence supporting the significant role of peripheral immune cell populations in AD pathology. Stalled brain capillaries with reduced blood flow seem to play a major role in cognitive function in different AD mouse models. Endothelium inflammation might be a possible cause of neutrophils accumulation in the AD mouse brain.

    The authors also suggested that capillary obstruction can happen due to peripheral tissue inflammation. We have observed a similar increase in Ly6C neutrophil population in the brain blood vessels of AD/arthritic mice (5XFAD/huTNF-overexpressing mice) caused by peripheral human TNF. Interestingly, administration of anti-TNF antibody to treat arthritis in the mice, by blocking circulating TNF, decreases Ly6C positive neutrophils in brain capillaries.

    In our model, peripheral inflammation seems to play a major role in the recruitment of neutrophils in the brain, and modulation of peripheral TNF levels can control this effect. Due to severe arthritis and short life span, cognitive evaluation of 5XFAD/ arthritic mice was not possible (Paouri et al., 2017; Süß, 2017). 

    We think this is an elegant study with important implications in interpreting the results of different studies on the role of anti-inflammatory drugs in AD. The authors have possibly provided a mechanism explaining the lower risk of AD that is observed in rheumatoid arthritis patients who take anti-TNF drugs, which possibly results in decreased neutrophil recruitment in brain capillaries and improved cognitive function. Of course, a lot of work is still needed to prove if this can be true.

    References:

    Paouri E, Tzara O, Kartalou GI, Zenelak S, Georgopoulos S. Peripheral Tumor Necrosis Factor-Alpha (TNF-α) Modulates Amyloid Pathology by Regulating Blood-Derived Immune Cells and Glial Response in the Brain of AD/TNF Transgenic Mice. J Neurosci. 2017 May 17;37(20):5155-5171. Epub 2017 Apr 25 PubMed.

    Süß P. Remote Control: Impacts of Peripheral Tumor Necrosis Factor-Alpha on Alzheimer Disease-Related Pathology. J Neurosci. 2017 Aug 23;37(34):8045-8047. PubMed.

    View all comments by Spiros Georgopoulos

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