Vasomotion Drives Periarterial Drainage of Aβ from the Brain
2020; Cell Press; Volume: 105; Issue: 3 Linguagem: Inglês
10.1016/j.neuron.2020.01.011
ISSN1097-4199
AutoresRoxana O. Carare, Roxana Aldea, Diederik Bulters, Aiman Alzetani, Anthony A. Birch, Giles Richardson, Roy O. Weller,
Tópico(s)Intracerebral and Subarachnoid Hemorrhage Research
ResumoIn this issue of Neuron, van Veluw et al., 2020van Veluw S.J. Hou S.S. Calvo-Rodriguez M. Arbel-Ornath M. Snyder A.C. Frosch M.P. Greenberg S.M. Bacskai B.J. Vasomotion as a Driving Force for Paravascular Clearance in the Awake Mouse Brain.Neuron. 2020; 105 (this issue): 549-561Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar show that elimination of solutes from the brain along arterial walls is driven by low-frequency arteriolar oscillations and suggest that age-related reduction of this vasomotion may contribute to impaired clearance of Aβ. In this issue of Neuron, van Veluw et al., 2020van Veluw S.J. Hou S.S. Calvo-Rodriguez M. Arbel-Ornath M. Snyder A.C. Frosch M.P. Greenberg S.M. Bacskai B.J. Vasomotion as a Driving Force for Paravascular Clearance in the Awake Mouse Brain.Neuron. 2020; 105 (this issue): 549-561Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar show that elimination of solutes from the brain along arterial walls is driven by low-frequency arteriolar oscillations and suggest that age-related reduction of this vasomotion may contribute to impaired clearance of Aβ. Age-related failure of the mechanisms for elimination of amyloid-β (Aβ) from the brain results in the accumulation of insoluble Aβ, and eventually soluble Aβ, both in the brain parenchyma and in the walls of the cerebral arteries. Aβ accumulation in the parenchyma leads to the development of Alzheimer's disease (AD) while its accumulation in the cerebral arteries is associated with cerebral amyloid angiopathy (CAA). In contrast to the rest of the body, the brain has no conventional lymphatics and instead solutes drain into cervical lymph nodes via the walls of cerebral arteries (Tarasoff-Conway et al., 2015Tarasoff-Conway J.M. Carare R.O. Osorio R.S. Glodzik L. Butler T. Fieremans E. Axel L. Rusinek H. Nicholson C. Zlokovic B.V. et al.Clearance systems in the brain-implications for Alzheimer disease.Nat. Rev. Neurol. 2015; 11: 457-470Crossref PubMed Scopus (843) Google Scholar). This is borne out by confocal and electron microscopy, which have been used to demonstrate that the anatomical pathways for drainage of solutes from the brain, including Aβ, are the basement membranes that surround smooth muscle cells (SMCs) in the tunica media (the intramural peri-arterial drainage [IPAD] pathway) (Albargothy et al., 2018Albargothy N.J. Johnston D.A. MacGregor-Sharp M. Weller R.O. Verma A. Hawkes C.A. Carare R.O. Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways.Acta Neuropathol. 2018; 136: 139-152Crossref PubMed Scopus (152) Google Scholar). The recent mathematical model from Aldea et al. suggests that vasomotion, defined as the spontaneous 0.1 Hz rhythmic oscillations in vascular tone (i.e., cycles of contraction and relaxation of SMC), could drive the clearance of solutes from the brain along IPAD pathways (Aldea et al., 2019Aldea R. Weller R.O. Wilcock D.M. Carare R.O. Richardson G. Cerebrovascular Smooth Muscle Cells as the Drivers of Intramural Periarterial Drainage of the Brain.Front. Aging Neurosci. 2019; 11: 1Crossref PubMed Scopus (97) Google Scholar). In the current issue of Neuron, van Veluw et al., 2020van Veluw S.J. Hou S.S. Calvo-Rodriguez M. Arbel-Ornath M. Snyder A.C. Frosch M.P. Greenberg S.M. Bacskai B.J. Vasomotion as a Driving Force for Paravascular Clearance in the Awake Mouse Brain.Neuron. 2020; 105 (this issue): 549-561Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar demonstrate, using two-photon microscopy, that vasomotion is a driving force for IPAD in vivo, with clearance of solutes from the brain in awake mice driven by ultra-slow arteriolar SMC oscillations (vasomotion). The clearance rate of fluorescent dextran, which had been delivered to IPAD paravascular pathways by temporary laser-induced extravasation, is shown to correlate with the amplitude of vasomotion in wild-type mice. Furthermore, when the amplitude of vasomotion is increased physiologically by functional hyperaemia, clearance rates also increase in wild-type mice. In the TgAPP/PS1 mice with CAA, there is impaired vasodilatation during functional hyperaemia, which is associated with slower clearance rates. The authors suggest that CAA is accompanied by loss of SMCs, which results in reduced vessel reactivity and impaired clearance along the walls of cerebral arterioles, termed paravascular clearance in the van Veluw paper. In the present study, van Veluw et al., 2020van Veluw S.J. Hou S.S. Calvo-Rodriguez M. Arbel-Ornath M. Snyder A.C. Frosch M.P. Greenberg S.M. Bacskai B.J. Vasomotion as a Driving Force for Paravascular Clearance in the Awake Mouse Brain.Neuron. 2020; 105 (this issue): 549-561Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar used in vivo two-photon microscopy and fluorescent angiograms, in conjunction with Fourier analysis, to demonstrate the presence of vasomotion in the SMCs of awake wild-type mice. This was observed to be spontaneous and specific to arterioles (not seen in venules). Furthermore, the arteriolar dilatations and constrictions had a distinct peak centered around 0.1 Hz. After a visual challenge consisting of a flashing checkerboard that resulted in functional hyperaemia, the vascular reactivity could be increased 5–10 times and was limited to the visual cortex. Using a novel approach based on the decay of fluorescent dextrans/fluorescein from irradiated vessels, rather than intracerebral injections of dyes, van Veluw et al., 2020van Veluw S.J. Hou S.S. Calvo-Rodriguez M. Arbel-Ornath M. Snyder A.C. Frosch M.P. Greenberg S.M. Bacskai B.J. Vasomotion as a Driving Force for Paravascular Clearance in the Awake Mouse Brain.Neuron. 2020; 105 (this issue): 549-561Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar demonstrate that in wild-type and 8- to 10-month-old adult APP/PS1 mice, the vasomotion observed at 0.1 Hz is responsible for the clearance along the walls of arteries. The authors observed that even 20-nm-diameter nanoparticles moved along the walls of arterioles against the direction of blood flow. However, the resolution of the two-photon microscope, which is lower than that of confocal/electron microscopes, is unable to detect the exact compartment in which the tracers are located. In 14-month-old APP/PS1 mice, vasomotion and clearance along the walls of arterioles were reduced. This correlates with the age-related decrease in the number of arterial SMCs and not with the onset of CAA. The findings in this paper validate the vasomotion hypothesis and mathematical model first proposed as the motive force for IPAD (Aldea et al., 2019Aldea R. Weller R.O. Wilcock D.M. Carare R.O. Richardson G. Cerebrovascular Smooth Muscle Cells as the Drivers of Intramural Periarterial Drainage of the Brain.Front. Aging Neurosci. 2019; 11: 1Crossref PubMed Scopus (97) Google Scholar). IPAD of interstitial fluid occurs along the basement membranes of capillaries and basement membranes surrounding SMCs, against the direction of blood flow (Morris et al., 2016Morris A.W. Sharp M.M. Albargothy N.J. Fernandes R. Hawkes C.A. Verma A. Weller R.O. Carare R.O. Vascular basement membranes as pathways for the passage of fluid into and out of the brain.Acta Neuropathol. 2016; 131: 725-736Crossref PubMed Scopus (191) Google Scholar). This pathway is restricted to soluble material, as nanoparticles of sizes greater than 15 nm remain in the pial-glial basement membranes on the outside of arteries in the brain (Morris et al., 2016Morris A.W. Sharp M.M. Albargothy N.J. Fernandes R. Hawkes C.A. Verma A. Weller R.O. Carare R.O. Vascular basement membranes as pathways for the passage of fluid into and out of the brain.Acta Neuropathol. 2016; 131: 725-736Crossref PubMed Scopus (191) Google Scholar). Two-photon microscopy is unable to resolve the different basement membranes within the walls of cerebral arteries, which is why van Veluw et al., 2020van Veluw S.J. Hou S.S. Calvo-Rodriguez M. Arbel-Ornath M. Snyder A.C. Frosch M.P. Greenberg S.M. Bacskai B.J. Vasomotion as a Driving Force for Paravascular Clearance in the Awake Mouse Brain.Neuron. 2020; 105 (this issue): 549-561Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar use the term "paravascular" rather than "IPAD." The position of the observed nanoparticles in the periarterial compartment, moving in the opposite direction to the blood flow, is most likely to be in the arterial pial-glial basement membranes and not in the basement membranes surrounding arterial SMCs. The authors show that, after irradiation, the fluorescent dextran diffuses in the extracellular space in the vicinity of the vascular trauma, but it is difficult to state whether the clearance of the dextran has occurred entirely along IPAD routes. In the context of amyloidosis, soluble Aβ is removed from the brain by various mechanisms including degradation by enzymes, crossing into the blood via LRP1 transporter, being taken up by macrophages, and drainage from the brain along the IPAD pathway (Tarasoff-Conway et al., 2015Tarasoff-Conway J.M. Carare R.O. Osorio R.S. Glodzik L. Butler T. Fieremans E. Axel L. Rusinek H. Nicholson C. Zlokovic B.V. et al.Clearance systems in the brain-implications for Alzheimer disease.Nat. Rev. Neurol. 2015; 11: 457-470Crossref PubMed Scopus (843) Google Scholar). As van Veluw et al., 2020van Veluw S.J. Hou S.S. Calvo-Rodriguez M. Arbel-Ornath M. Snyder A.C. Frosch M.P. Greenberg S.M. Bacskai B.J. Vasomotion as a Driving Force for Paravascular Clearance in the Awake Mouse Brain.Neuron. 2020; 105 (this issue): 549-561Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar measure the clearance of solutes similar to Aβ over 20 min, it is impossible to state which of the aforementioned clearance mechianisms is the dominant one; in fact, it is likely that they all play a significant role within this time frame. Visual stimulation increases the cerebral blood flow after a cascade of molecular events involving calcium that may also affect the activity of LRP1 on the arterial SMCs or stimulate other mechanisms of clearance beside IPAD. van Veluw et al., 2020van Veluw S.J. Hou S.S. Calvo-Rodriguez M. Arbel-Ornath M. Snyder A.C. Frosch M.P. Greenberg S.M. Bacskai B.J. Vasomotion as a Driving Force for Paravascular Clearance in the Awake Mouse Brain.Neuron. 2020; 105 (this issue): 549-561Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar are also able to demonstrate that the reduction in vasomotion in the transgenic APP/PS1 model of CAA coincides with the reduction in the number of the arterial SMCs and not with the onset of CAA. In CAA, the deposition of Aβ in the walls of cerebral arteries starts in the basement membranes surrounding the SMCs and continues to spread radially throughout the arterial wall until the artery wall is devoid of its normal elements and is formed almost entirely by deposits of fibrillar Aβ (Frackowiak et al., 1994Frackowiak J. Zoltowska A. Wisniewski H.M. Non-fibrillar beta-amyloid protein is associated with smooth muscle cells of vessel walls in Alzheimer disease.J. Neuropathol. Exp. Neurol. 1994; 53: 637-645Crossref PubMed Scopus (122) Google Scholar). Since there appears to be no overproduction of Aβ in sporadic CAA, it is the failure of clearance of Aβ that is responsible for accumulation of amyloid in the walls of cerebral and leptomeningeal arteries. This failure of the IPAD clearance pathways occurs with increasing age, with possession of apolipoprotein E4 genotype, and after immunization against Aβ (Hawkes et al., 2011Hawkes C.A. Härtig W. Kacza J. Schliebs R. Weller R.O. Nicoll J.A. Carare R.O. Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy.Acta Neuropathol. 2011; 121: 431-443Crossref PubMed Scopus (243) Google Scholar, Hawkes et al., 2012Hawkes C.A. Sullivan P.M. Hands S. Weller R.O. Nicoll J.A. Carare R.O. Disruption of arterial perivascular drainage of amyloid-β from the brains of mice expressing the human APOE ε4 allele.PLoS ONE. 2012; 7: e41636Crossref PubMed Scopus (130) Google Scholar, Carare et al., 2013Carare R.O. Teeling J.L. Hawkes C.A. Püntener U. Weller R.O. Nicoll J.A. Perry V.H. Immune complex formation impairs the elimination of solutes from the brain: implications for immunotherapy in Alzheimer's disease.Acta Neuropathol. Commun. 2013; 1: 48Crossref Scopus (35) Google Scholar). There is little evidence of a decrease in the number of SMCs in the arteries of aging human brains. In humans, the decrease in function of the arterial SMCs arising from vascular risk factors, such as fibrosis in small vessel disease or arteriolosclerosis, combined with the changes in the biochemical properties of the basement membranes is the most likely trigger for the failure of IPAD clearance along the basement membranes surrounding arterial SMCs (Sweeney et al., 2019Sweeney M.D. Montagne A. Sagare A.P. Nation D.A. Schneider L.S. Chui H.C. Harrington M.G. Pa J. Law M. Wang D.J.J. et al.Vascular dysfunction-The disregarded partner of Alzheimer's disease.Alzheimers Dement. 2019; 15: 158-167Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar). The experimental evidence in mice produced in the paper by van Veluw et al., 2020van Veluw S.J. Hou S.S. Calvo-Rodriguez M. Arbel-Ornath M. Snyder A.C. Frosch M.P. Greenberg S.M. Bacskai B.J. Vasomotion as a Driving Force for Paravascular Clearance in the Awake Mouse Brain.Neuron. 2020; 105 (this issue): 549-561Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar contributes significantly to our understanding of the mechanisms for drainage of solutes from the brain along the walls of arteries with particular implications for the clearance of Aβ and its age-related failure. In addition, the findings confirm that drainage of solutes occurs along the arteries but not along the veins. However, further work remains to be done. For example, while the study provides strong experimental evidence to back the hypothesis that arterial vasomotion is the driving force for IPAD in mice, the 0.1 Hz oscillations remain to be demonstrated in the human brain. Elucidating the mechanisms by which Aβ—and, potentially, other toxic solutes associated with diverse proteinopathies—is eliminated from the brain along the walls of arteries and why these mechanisms fail with age is essential if therapeutic strategies are to be designed to prevent and manage AD and CAA. The work by van Veluw et al., 2020van Veluw S.J. Hou S.S. Calvo-Rodriguez M. Arbel-Ornath M. Snyder A.C. Frosch M.P. Greenberg S.M. Bacskai B.J. Vasomotion as a Driving Force for Paravascular Clearance in the Awake Mouse Brain.Neuron. 2020; 105 (this issue): 549-561Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar is a significant step in this direction. Vasomotion as a Driving Force for Paravascular Clearance in the Awake Mouse Brainvan Veluw et al.NeuronDecember 3, 2019In Briefvan Veluw et al. demonstrate that vasomotion is a major driving force for paravascular clearance of solutes from the brain. Loss of vascular smooth muscle cells and reduced vasomotion in the context of amyloid deposition is associated with impaired clearance. Full-Text PDF Open Archive
Referência(s)