Nortley R, Korte N, Izquierdo P, Hirunpattarasilp C, Mishra A, Jaunmuktane Z, Kyrargyri V, Pfeiffer T, Khennouf L, Madry C, Gong H, Richard-Loendt A, Huang W, Saito T, Saido TC, Brandner S, Sethi H, Attwell D. Amyloid β oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes. Science. 2019 Jul 19;365(6450) Epub 2019 Jun 20 PubMed.

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  1. The story of the vascular effects of Aβ is evolving steadily, and the present paper, in conjunction with the paper of Cruz Hernández et al., 2019, represents the latest chapters.

    It has been known for a while that Aβ is a vasoconstrictor acting through free radicals derived from NADPH oxidase, and that counteracting these vascular effects rescues cognitive impairment in mouse models of Aβ accumulation, attesting to their pathogenic relevance (Park et al., 2005; Park et al., 2008). Subsequent studies identified the Aβ-binding scavenger receptor CD36 and NOX2 in perivascular macrophage associated with resistance arterioles as the source of the radicals and contributing to the neurovascular dysfunction (Park et al., 2011; Park et al., 2017). The ultimate effector of the dysfunction, downstream of radicals, was identified to be dysregulated opening of the TRPM2 channels and Ca2+ overload in cerebral endothelial cells (Park et al., 2014). 

    The present study extends these observations in several respects. First, it implicates vasoactivity of capillaries in the microvascular effects of Aβ. Second, it identifies capillary mural cells, such as pericytes, as critical for the capillary constriction. Third, it suggests that in these cells NOX4, rather than NOX2, is the source of the radicals involved in the capillary constriction. Fourth, and most importantly, it verifies some of these observations in freshly collected human brain samples. The importance of capillaries as a relevant microvascular site for the effects of Aβ on cerebral perfusion is also suggested by the Cruz Hernández study, demonstrating that transient occlusions of capillaries by circulating leukocytes (capillary stalling) contributes to the cerebral hypoperfusion associated with Aβ accumulation, and that counteracting the stalling rescues the reduction of cerebral blood flow and cognitive function in mice overexpressing APP (Cruz Hernández et al., 2019). 

    These observations, in concert with accumulating evidence of blood-brain barrier dysfunction in AD (Nation et al., 2019) and capillary transit time abnormality (Gutiérrez-Jiménez et al., 2018), point to an emerging role of cerebral capillaries in the vascular pathobiology of Aβ and reinforce the idea that Aβ acts at all levels of the cerebrovascular tree and on different cells to exert its deleterious effects on the brain circulation. Evidence demonstrating that rescuing the pericyte contribution to this process ameliorates cognitive function would be the next step in building the case that targeting pericytes and capillary vasoactivity is a viable strategy to counteract the neurovascular dysfunction induced by Aβ.

    References:

    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.

    Park L, Anrather J, Zhou P, Frys K, Pitstick R, Younkin S, Carlson GA, Iadecola C. NADPH-oxidase-derived reactive oxygen species mediate the cerebrovascular dysfunction induced by the amyloid beta peptide. J Neurosci. 2005 Feb 16;25(7):1769-77. PubMed.

    Park L, Zhou P, Pitstick R, Capone C, Anrather J, Norris EH, Younkin L, Younkin S, Carlson G, McEwen BS, Iadecola C. Nox2-derived radicals contribute to neurovascular and behavioral dysfunction in mice overexpressing the amyloid precursor protein. Proc Natl Acad Sci U S A. 2008 Jan 29;105(4):1347-52. PubMed.

    Park L, Wang G, Zhou P, Zhou J, Pitstick R, Previti ML, Younkin L, Younkin SG, Van Nostrand WE, Cho S, Anrather J, Carlson GA, Iadecola C. Scavenger receptor CD36 is essential for the cerebrovascular oxidative stress and neurovascular dysfunction induced by amyloid-beta. Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):5063-8. PubMed.

    Park L, Uekawa K, Garcia-Bonilla L, Koizumi K, Murphy M, Pistik R, Younkin L, Younkin S, Zhou P, Carlson G, Anrather J, Iadecola C. Brain Perivascular Macrophages Initiate the Neurovascular Dysfunction of Alzheimer Aβ Peptides. Circ Res. 2017 Jul 21;121(3):258-269. Epub 2017 May 17 PubMed.

    Park L, Wang G, Moore J, Girouard H, Zhou P, Anrather J, Iadecola C. The key role of transient receptor potential melastatin-2 channels in amyloid-β-induced neurovascular dysfunction. Nat Commun. 2014 Oct 29;5:5318. PubMed.

    Nation DA, Sweeney MD, Montagne A, Sagare AP, D'Orazio LM, Pachicano M, Sepehrband F, Nelson AR, Buennagel DP, Harrington MG, Benzinger TL, Fagan AM, Ringman JM, Schneider LS, Morris JC, Chui HC, Law M, Toga AW, Zlokovic BV. Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat Med. 2019 Feb;25(2):270-276. Epub 2019 Jan 14 PubMed.

    Gutiérrez-Jiménez E, Angleys H, Rasmussen PM, West MJ, Catalini L, Iversen NK, Jensen MS, Frische S, Østergaard L. Disturbances in the control of capillary flow in an aged APPswe /PS1ΔE9 model of Alzheimer's disease. Neurobiol Aging. 2018 Feb;62:82-94. Epub 2017 Oct 16 PubMed.

    View all comments by Costantino Iadecola

  2. Vasoactive properties of peptides have been known for more than 20 years. For example, in the mid-1990s Aβ peptides were shown to induce vasoconstriction in the isolated rat aorta, which was ameliorated by superoxide dismutase 1 (SOD1) implicating involvement of reactive oxygen species (ROS) (Thomas et al., 1996). The follow-up studies in young Tg2576 mice overexpressing human APP (Swedish mutation) indicated that Aβ reduces cerebrovascular reactivity to endothelium-dependent vasodilators (for example, acetylcholine, bradykinin, or calcium ionophore A23187) and increases response to vasoconstrictors acting directly on vascular smooth muscle cells (VSMCs) (for example, the thromboxane A2 analogue U46619) (Zhang et al., 1997; Iadecola et al., 1999), that was associated with impaired neurovascular coupling (the dynamic functional change in cerebral blood flow that occurs in response to local neuronal activity) (Niwa et al., 2000). These abnormal vascular responses could again be rescued with SOD1, confirming involvement of ROS in vivo (Iadecola et al. 1999). Collectively, these pioneering studies suggest that accumulation of low levels of soluble Aβ (likely Aβ oligomeric species) before Aβ deposition leads to a global impairment of vascular responses. Moreover, in the brain endothelium Aβ-mediated oxidant stress led to proinflammatory changes in cerebral blood vessels and generation of endothelin 1 (ET1) through the receptor for advanced glycosylation end products (RAGE), which binds Aβ, that was shown to lead to cerebral blood flow (CBF) reductions in Tg2576 mice in vivo (Deane et al., 2003, 2012). Based on these findings (Deane et al., 2003), a clinical Phase 2/3 trial with a RAGE blocker in patients with mild Alzheimer’s disease and impaired glucose tolerance (NCT03980730 June 2019–July 2023) has been recently initiated.

    Here, Nortley et al. importantly confirmed that Aβ generates ROS in rat brain slices, which evoked release of ET1 and activated ETa receptor in pericytes to cause capillary constriction, consistent with the proposed mechanism of ET1 activation of pericytes, as we recently reviewed (Kisler et al., 2017, see Figure 3). They extended studies to live healthy human brain slices, and human tissue derived from individuals with cognitive decline to show capillary constriction in areas rich with Aβ deposits close to PDGRFβ -positive pericytes, but not aSMA-positive arterioles. Interestingly, the authors only show that constriction occurs in capillaries in vivo, in contrast to their ex vivo data and previous reports implicating ROS-mediated vascular dysfunction in arterioles as well.

    Although Nortley et al. propose that the ET1 pathway in pericytes could be a key mechanism implicated in neurodegeneration, they did not show any neuron and/or synaptic loss in their study, thus leaving open the question whether the proposed ET1-ETa mechanism can drive neurodegeneration. It has been reported, however, that accelerated pericyte loss in Tg2576 APP mice leads to both tau pathology and an overt neuron loss, suggesting that vascular damage caused by pericyte loss is a second hit in the disease process leading to neuron loss and degenerative changes in this AD model that otherwise does not occur (Sagare et al., 2013). 

    Other neuropathological studies in AD brain tissue have shown loss of pericytes associated with blood-brain barrier (BBB) breakdown and accumulation of Aβ deposits (Sengillo et al. 2013; Halliday et al. 2015). It has also been shown that Aβ intracellular accumulation kills pericytes (Ma et al., 2018; Sagare et al., 2013). Thus, while interesting, it remains to be seen how findings that Nortley et al. report fit with the existing knowledge in the field.

    References:

    Thomas T, Thomas G, McLendon C, Sutton T, Mullan M. beta-Amyloid-mediated vasoactivity and vascular endothelial damage. Nature. 1996 Mar 14;380(6570):168-71. PubMed.

    Zhang F, Eckman C, Younkin S, Hsiao KK, Iadecola C. Increased susceptibility to ischemic brain damage in transgenic mice overexpressing the amyloid precursor protein. J Neurosci. 1997 Oct 15;17(20):7655-61. PubMed.

    Iadecola C, Zhang F, Niwa K, Eckman C, Turner SK, Fischer E, Younkin S, Borchelt DR, Hsiao KK, Carlson GA. SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein. Nat Neurosci. 1999 Feb;2(2):157-61. PubMed.

    Niwa K, Younkin L, Ebeling C, Turner SK, Westaway D, Younkin S, Ashe KH, Carlson GA, Iadecola C. Abeta 1-40-related reduction in functional hyperemia in mouse neocortex during somatosensory activation. Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9735-40. PubMed.

    Deane R, Du Yan S, Submamaryan RK, LaRue B, Jovanovic S, Hogg E, Welch D, Manness L, Lin C, Yu J, Zhu H, Ghiso J, Frangione B, Stern A, Schmidt AM, Armstrong DL, Arnold B, Liliensiek B, Nawroth P, Hofman F, Kindy M, Stern D, Zlokovic B. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med. 2003 Jul;9(7):907-13. PubMed.

    Deane R, Singh I, Sagare AP, Bell RD, Ross NT, LaRue B, Love R, Perry S, Paquette N, Deane RJ, Thiyagarajan M, Zarcone T, Fritz G, Friedman AE, Miller BL, Zlokovic BV. A multimodal RAGE-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of Alzheimer disease. J Clin Invest. 2012 Apr 2;122(4):1377-92. PubMed.

    Kisler K, Nelson AR, Montagne A, Zlokovic BV. Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat Rev Neurosci. 2017 Jul;18(7):419-434. Epub 2017 May 18 PubMed.

    Sagare AP, Bell RD, Zhao Z, Ma Q, Winkler EA, Ramanathan A, Zlokovic BV. Pericyte loss influences Alzheimer-like neurodegeneration in mice. Nat Commun. 2013;4:2932. PubMed. Correction. RETRACTED

    Sengillo JD, Winkler EA, Walker CT, Sullivan JS, Johnson M, Zlokovic BV. Deficiency in Mural Vascular Cells Coincides with Blood-Brain Barrier Disruption in Alzheimer's Disease. Brain Pathol. 2012 Nov 5; PubMed.

    Halliday MR, Rege SV, Ma Q, Zhao Z, Miller CA, Winkler EA, Zlokovic BV. Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer's disease. J Cereb Blood Flow Metab. 2015 Mar 11; PubMed.

    Ma Q, Zhao Z, Sagare AP, Wu Y, Wang M, Owens NC, Verghese PB, Herz J, Holtzman DM, Zlokovic BV. Blood-brain barrier-associated pericytes internalize and clear aggregated amyloid-β42 by LRP1-dependent apolipoprotein E isoform-specific mechanism. Mol Neurodegener. 2018 Oct 19;13(1):57. PubMed. Correction. Correction.

    Sagare AP, Bell RD, Zhao Z, Ma Q, Winkler EA, Ramanathan A, Zlokovic BV. Pericyte loss influences Alzheimer-like neurodegeneration in mice. Nat Commun. 2013;4:2932. PubMed. Correction. RETRACTED

    View all comments by Kassandra Kisler

  3. Vascular abnormalities have been observed in dementia since the seminal studies of Alois Alzheimer and Oscar Fisher in the early 1900s. However, vascular abnormalities have often taken a back seat to the more prominent pathologies of amyloid plaques and neurofibrillary tangles. Yet, from numerous studies it is emerging that vascular dysfunction likely has a causal role neurodegeneration and dementia (Nation et al., 2019). Recent findings from David Attwell’s laboratory underscore this point and implicate pericytes in cerebral vascular constrictions that likely contribute to cognitive impairment.

    Nortley and colleagues provide compelling evidence that in humans elevated Aβ induces pericytes to constrict brain microvasculature leading to ischemic brain regions which could contribute to neuronal damage and synaptic loss in AD. This fits into emerging evidence that vascular dysfunction has a prominent role in neurodegeneration and in particular targeting pericytes may be a viable strategy to counteract cognitive impairments induced by neurovascular dysfunction (Bell et al., 2012; Halliday et al., 2015). 

    Conversely as the authors note, this study suggests that pericytes may also have a role in cognitive resilience. Numerous aged humans accumulate high levels of Aβ but seemingly do not develop cognitive impairments. It is interesting to speculate that pericytes could play a role whereby among human genetic diversity there are individuals endowed with “protective” pericytes that do not constrict in response to Aβ or are prone to compensatory vasodilation. Delving into pericyte biology and how human genetic diversity influences their contributions to pathophysiology certainly promises to be an exciting future direction.

    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.

    Halliday MR, Rege SV, Ma Q, Zhao Z, Miller CA, Winkler EA, Zlokovic BV. Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer's disease. J Cereb Blood Flow Metab. 2015 Mar 11; PubMed.

    Nation DA, Sweeney MD, Montagne A, Sagare AP, D'Orazio LM, Pachicano M, Sepehrband F, Nelson AR, Buennagel DP, Harrington MG, Benzinger TL, Fagan AM, Ringman JM, Schneider LS, Morris JC, Chui HC, Law M, Toga AW, Zlokovic BV. Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat Med. 2019 Feb;25(2):270-276. Epub 2019 Jan 14 PubMed.

    View all comments by Joel Blanchard

  4. The missing link. This is a must-read article on the convergence between the amyloid dysmetabolism and vascular dysfunctions.

    View all comments by Stefano Sensi

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