Cerebral blood flow decrease as an early pathological mechanism in Alzheimer's disease

1.

Abdullah L, Crawford F, Tsolaki M, Börjesson-Hanson A, Olde Rikkert M, Pasquier F et al (2020) The Influence of baseline Alzheimer’s disease severity on cognitive decline and CSF biomarkers in the NILVAD trial. Front Neurol 11:149. https://doi.org/10.3389/fneur.2020.00149CrossRefPubMedPubMedCentral

2.

Akenhead ML, Horrall NM, Rowe D, Sethu P, Shin HY (2015) In vitro evaluation of the link between cell activation state and its rheological Impact on the microscale flow of neutrophil suspensions. J Biomech Eng 137:91003. https://doi.org/10.1115/1.4030824CrossRef

3.

Alarcon-Martinez L, Yilmaz-Ozcan S, Yemisci M, Schallek J, Kilic K, Can A et al (2018) Capillary pericytes express α-smooth muscle actin, which requires prevention of filamentous-actin depolymerization for detection. Elife 7:e34861. https://doi.org/10.7554/eLife.34861.001CrossRefPubMedPubMedCentral

4.

Armulik A, Genové G, Mäe M, Nisancioglu MH, Wallgard E, Niaudet C et al (2010) Pericytes regulate the blood-brain barrier. Nature 468:557–561. https://doi.org/10.1038/nature09522CrossRefPubMed

5.

Asllani I, Habeck C, Scarmeas N, Borogovac A, Brown TR, Stern Y (2008) Multivariate and univariate analysis of continuous arterial spin labeling perfusion MRI in Alzheimer’s disease. J Cereb Blood Flow Metab 28:725–736. https://doi.org/10.1038/sj.jcbfm.9600570CrossRefPubMed

6.

Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar M et al (2015) A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med 212:991–999. https://doi.org/10.1084/jem.20142290CrossRefPubMedPubMedCentral

7.

Attems J, Lintner F, Jellinger KA (2004) Amyloid beta peptide 1–42 highly correlates with capillary cerebral amyloid angiopathy and Alzheimer disease pathology. Acta Neuropathol 107:283–291. https://doi.org/10.1007/s00401-004-0822-6CrossRefPubMed

8.

Attwell D, Laughlin SB (2001) An energy budget for signaling in the grey matter of the brain. J Cereb Blood Flow Metab 21:1133–1145. https://doi.org/10.1097/00004647-200110000-00001CrossRefPubMed

9.

Attwell D, Mishra A, Hall CN, O’Farrell FM, Dalkara T (2016) What is a pericyte? J Cereb Blood Flow Metab 36:451–455. https://doi.org/10.1177/0271678X15610340CrossRefPubMed

10.

Barnham KJ, Masters CL, Bush CI (2004) Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov 3:205–214. https://doi.org/10.1038/nrd1330CrossRefPubMed

11.

Beason-Held LL, Goh JO, An Y, Kraut MA, O’Brien RJ, Ferrucci L et al (2013) Changes in brain function occur years before the onset of cognitive impairment. J Neurosci 33:18008–18014. https://doi.org/10.1523/JNEUROSCI.1402-13.2013CrossRefPubMedPubMedCentral

12.

Belarbi K, Cuvelier E, Destée A, Gressier B, Chartier-Harlin M-C (2017) NADPH oxidases in Parkinson’s disease: a systematic review. Mol Neurodegener 12:84. https://doi.org/10.1186/s13024-017-0225-5CrossRefPubMedPubMedCentral

13.

Bell RD, Winkler EA, Sagare AP, Singh I, LaRue B, Deane R et al (2010) Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 68:409–427. https://doi.org/10.1016/j.neuron.2010.09.043CrossRefPubMedPubMedCentral

14.

Bosco DA, Fowler DM, Zhang Q, Nieva J, Powers ET, Wentworth P et al (2006) Elevated levels of oxidized cholesterol metabolites in Lewy body disease brains accelerate alpha-synuclein fibrilization. Nat Chem Biol 2:249–253. https://doi.org/10.1038/nchembio782CrossRefPubMed

15.

Bracko O, Njiru BN, Swallow M, Ali M, Haft-Javaherian M, Schaffer CB (2019) Increasing cerebral blood flow improves cognition into late stages in Alzheimer’s disease mice. J Cereb Blood Flow Metab 40:1441–1452. https://doi.org/10.1177/0271678X19873658CrossRefPubMedPubMedCentral

16.

Braide M, Amundson B, Chien S, Bagge U (1984) Quantitative studies on the influence of leukocytes on the vascular resistance in a skeletal muscle preparation. Microvasc Res 27:331–352. https://doi.org/10.1016/0026-2862(84)90064-5CrossRefPubMed

17.

Bressi S, Volontè M, Alberoni M, Canal N, Franceschi M (1992) Transcranial Doppler sonography in the early phase of Alzheimer’s disease. Dement Geriatr Cogn Discord 3:25–31. https://doi.org/10.1177/0271678X19873658CrossRef

18.

Brickman AM, Provenzano FA, Muraskin J, Manly JJ, Blum S, Apa Z et al (2012) Regional white matter hyperintensity volume, not hippocampal atrophy, predicts incident Alzheimer disease in the community. Arch Neurol 69:1621–1627. https://doi.org/10.1001/archneurol.2012.1527CrossRefPubMedPubMedCentral

19.

Busche MA, Chen X, Henning HA, Reichwald J, Staufenbiel M, Sakmann B et al (2012) Critical role of soluble amyloid-β for early hippocampal hyperactivity in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 109:8740–8745. https://doi.org/10.1073/pnas.1206171109CrossRefPubMedPubMedCentral

20.

Busche MA, Eichhoff G, Adelsberger H, Abramowski D, Wiederhold K-H, Haass C et al (2008) Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer’s disease. Science 321:1686–1689. https://doi.org/10.1126/science.1162844CrossRefPubMed

21.

Busche MA, Wegmann S, Dujardin S, Commins C, Schiantarelli J, Klickstein N et al (2019) Tau impairs neural circuits, dominating amyloid-β effects, in Alzheimer models in vivo. Nat Neurosci 22:57–64. https://doi.org/10.1038/s41593-018-0289-8CrossRefPubMed

22.

Casey CS, Atagi Y, Yamazaki Y, Shinohara M, Tachibana M, Fu Y et al (2015) Apolipoprotein E inhibits cerebrovascular motility through a RhoA protein-mediated pathway. JBiol Chem 290:14208–14217. https://doi.org/10.1074/jbc.M114.625251CrossRef

23.

Cheng X, He P, Lee T, Yao H, Li R, Shen Y (2014) High activities of BACE1 in brains with mild cognitive impairment. Am J Pathol 184:141–147. https://doi.org/10.1016/j.ajpath.2013.10.002CrossRefPubMedPubMedCentral

24.

Collins-Praino LE, Francis YI, Griffith EY, Wiegman AF, Urbach J, Lawton A et al (2014) Soluble amyloid beta levels are elevated in the white matter of Alzheimer’s patients, independent of cortical plaque severity. Acta Neuropathol Commun 2:83. https://doi.org/10.1186/s40478-014-0083-0CrossRefPubMedPubMedCentral

25.

Cortes-Canteli M, Kruyer A, Fernandez-Nueda I, Marcos-Diaz A, Ceron C, Richards AT et al (2019) Long-term dabigatran treatment delays Alzheimer’s disease pathogenesis in the TgCRND8 mouse model. J Am Coll Cardiol 74:1910–1923. https://doi.org/10.1016/j.jacc.2019.07.081CrossRefPubMedPubMedCentral

26.

Cruz Hernández JC, Bracko O, Kersbergen CJ, Muse V, Haft-Javaherian M, Berg M et al (2019) Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer’s disease mouse models. Nat Neurosci 22:413–420. https://doi.org/10.1038/s41593-018-0329-4CrossRefPubMedPubMedCentral

27.

Dai W, Lopez OL, Carmichael OT, Becker JT, Kuller LH, Gach HM (2008) Abnormal regional cerebral blood flow in cognitively normal elderly subjects with hypertension. Stroke 39:349–354. https://doi.org/10.1161/STROKEAHA.107.495457CrossRefPubMedPubMedCentral

28.

Da Mesquita S, Louveau A, Vaccari A, Smirnov I, Cornelison RC, Kingsmore KM et al (2018) Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature 560:185–191. https://doi.org/10.1038/s41586-018-0368-8CrossRefPubMedPubMedCentral

29.

de Jong DLK, de Heus RAA, Rijpma A, Donders R, Olde Rikkert MGM, Günther M et al (2019) Effects of nilvadipine on cerebral blood flow in patients With Alzheimer disease. Hypertension 74:413–420. https://doi.org/10.1161/HYPERTENSIONAHA.119.12892CrossRefPubMed

30.

de la Monte SM (1989) Quantitation of cerebral atrophy in preclinical and end-stage Alzheimer’s disease. Ann Neurol 25:450–459. https://doi.org/10.1002/ana.410250506CrossRefPubMed

31.

de la Torre JC, Mussivand T (1993) Can disturbed brain microcirculation cause Alzheimer’s disease? Neurol Res 15:146–153. https://doi.org/10.1080/01616412.1993.11740127CrossRefPubMed

32.

Deane R, Du Yan S, Submamaryan RK, LaRue B, Jovanovic S, Hogg E et al (2003) RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med 9:907–913. https://doi.org/10.1038/nm890CrossRefPubMed

33.

Desai RA, Davies AL, Del Rossi N, Tachrount M, Dyson A, Gustavson B et al (2020) Nimodipine reduces dysfunction and demyelination in models of multiple sclerosis. Ann Neurol 88:123–136. https://doi.org/10.1002/ana.25749CrossRefPubMedPubMedCentral

34.

D’haeseleer M, Beelen R, Fierens Y, Cambron M, Vanbinst AM, Verborgh C et al (2013) Cerebral hypoperfusion in multiple sclerosis is reversible and mediated by endothelin-1. Proc Natl Acad Sci USA 110:5654–5658. https://doi.org/10.1073/pnas.1222560110CrossRefPubMedPubMedCentral

35.

Dhiman K, Gupta VB, Villemagne VL, Eratne D, Graham PL, Fowler C et al (2020) Cerebrospinal fluid neurofilament light concentration predicts brain atrophy and cognition in Alzheimer’s disease. Alzheimers Dement 12:e12005. https://doi.org/10.1002/dad2.12005CrossRef

36.

Diem AK, MacGregor Sharp M, Gatherer M, Bressloff NW, Carare RO, Richardson G (2017) Arterial pulsations cannot drive intramural periarterial drainage: significance for Aβ drainage. Front Neurosci 11:475. https://doi.org/10.3389/fnins.2017.00475CrossRefPubMedPubMedCentral

37.

Engler RL, Dahlgren MD, Morris DD, Peterson MA, Schmid-Schönbein GW (1986) Role of leukocytes in response to acute myocardial ischemia and reflow in dogs. Am J Physiol 251:H314–323. https://doi.org/10.1152/ajpheart.1986.251.2.H314CrossRefPubMed

38.

Eskildsen SF, Gyldensted L, Nagenthiraja K, Nielsen RB, Hansen MB, Dalby RB et al (2017) Increased cortical capillary transit time heterogeneity in Alzheimer’s disease: a DSC-MRI perfusion study. Neurobiol Aging 50:107–118. https://doi.org/10.1016/j.neurobiolaging.2016.11.004CrossRefPubMed

39.

Esparza TJ, Zhao H, Cirrito JR, Cairns NJ, Bateman RJ, Holtzman DM et al (2013) Amyloid-β oligomerization in Alzheimer dementia versus high-pathology controls. Ann Neurol 73:104–119. https://doi.org/10.1002/ana.23748CrossRefPubMed

40.

Fazlollahi A, Calamante F, Liang X, Bourgeat P, Raniga P, Dore V et al (2020) Increased cerebral blood flow with increased amyloid burden in the preclinical phase of Alzheimer’s disease. J Magn Reson Imaging 51:505–513. https://doi.org/10.1002/jmri.26810CrossRefPubMed

41.

Fernandez-Klett F, Potas JR, Hilpert D, Blazej K, Radke J, Huck J et al (2013) Early loss of pericytes and perivascular stromal cell-induced scar formation after stroke. J Cereb Blood Flow Metab 33:428–439. https://doi.org/10.1038/jcbfm.2012.187CrossRefPubMed

42.

Firbank MJ, Colloby SJ, Burn DJ, McKeith IG, O’Brien JT (2003) Regional cerebral blood flow in Parkinson’s disease with and without dementia. Neuroimage 20:1309–1319. https://doi.org/10.1016/S1053-8119(03)00364-1CrossRefPubMed

43.

Fowler JC (1990) Adenosine antagonists alter the synaptic response to in vitro ischemia in the rat hippocampus. Brain Res 509:331–334. https://doi.org/10.1016/0006-8993(90)90560-XCrossRefPubMed

44.

Friberg L, Rosenqvist M (2018) Less dementia with oral anticoagulation in atrial fibrillation. Eur Heart J 39:453–460. https://doi.org/10.1093/eurheartj/ehx579CrossRefPubMed

45.

Fulop GA, Tarantini S, Yabluchanskiy A, Molnar A, Prodan CI, Kiss T et al (2019) Role of age-related alterations of the cerebral venous circulation in the pathogenesis of vascular cognitive impairment. Am J Physiol Heart Circ Physiol 316:H1124–H1140. https://doi.org/10.1152/ajpheart.00776.2018CrossRefPubMedPubMedCentral

46.

Garcia-Alloza M, Gregory J, Kuchibhotla JV, Fine S, Wei Y, Ayata C et al (2011) Cerebrovascular lesions induce transient β-amyloid deposition. Brain 134:3697–3707. https://doi.org/10.1093/brain/awr300CrossRefPubMed

47.

Gauthier S, Feldman HH, Schneider LS, Wilcock GK, Frisoni GB, Hardlund JH et al (2016) Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer’s disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial. Lancet 388:2873–2884. https://doi.org/10.1016/S0140-6736(16)31275-2CrossRefPubMedPubMedCentral

48.

Girouard H, Iadecola C (2006) Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. J Appl Physiol 100:328–335. https://doi.org/10.1152/japplphysiol.00966.2005CrossRefPubMed

49.

Gould IG, Tsai P, Kleinfeld D, Linninger A (2017) The capillary bed offers the largest hemodynamic resistance to the cortical blood supply. J Cereb Blood Flow Metab 37:52–68. https://doi.org/10.1177/0271678X16671146CrossRefPubMed

50.

Greenberg SM, Bacskai BJ, Hernandez-Guillamon M, Pruzin J, Sperling R, van Velew SJ (2020) Cerebral amyloid angiopathy and Alzheimer disease—one peptide, two pathways. Nat Rev Neurol 16:30–42. https://doi.org/10.1038/s41582-019-0281-2CrossRefPubMed

51.

Greenberg SM, Charidimou A (2018) Diagnosis of cerebral amyloid angiopathy: evolution of the Boston criteria. Stroke 49:491–497. https://doi.org/10.1161/STROKEAHA.117.016990CrossRefPubMedPubMedCentral

52.

Guo T, Noble W, Hanger DP (2017) Roles of tau protein in health and disease. Acta Neuropathol 133:665–704. https://doi.org/10.1007/s00401-017-1707-9CrossRefPubMedPubMedCentral

53.

Guo Y, Li X, Zhang M, Chen N, Wu S, Lei J et al (2019) Age- and brain region-associated alterations of cerebral blood flow in early Alzheimer’s disease assessed in AβPPSWE/PS1ΔE9 transgenic mice using arterial spin labeling. Mol Med Rep 19:3045–3052. https://doi.org/10.3892/mmr.2019.9950CrossRefPubMedPubMedCentral

54.

Gutiérrez-Jiménez E, Angleys H, Rasmussen PM, West MJ, Catalini L, Iversen NK et al (2018) Disturbances in the control of capillary flow in an aged APPswe/PS1ΔE9 model of Alzheimer’s disease. Neurobiol Aging 62:82–94. https://doi.org/10.1016/j.neurobiolaging.2017.10.006CrossRefPubMed

55.

Haft-Javaherian M, Fang L, Muse V, Schaffer CB, Nishimura N, Sabuncu MR (2019) Deep convolutional neural networks for segmenting 3D in vivo multiphoton images of vasculature in Alzheimer disease mouse models. PLoS ONE 14:e0213539. https://doi.org/10.1371/journal.pone.0213539CrossRefPubMedPubMedCentral

56.

Hall CN, Reynell C, Gesslein B, Hamilton NB, Mishra A, Sutherland BA et al (2014) Capillary pericytes regulate cerebral blood flow in health and disease. Nature 508:55–60. https://doi.org/10.1038/nature13165CrossRefPubMedPubMedCentral

57.

Hanseeuw BJ, Betensky RA, Jacobs HIL, Schultz AP, Sepulcre J, Becker JA et al (2019) Association of amyloid and tau with cognition in preclinical Alzheimer disease: a longitudinal study. JAMA Neurol 76:915–924. https://doi.org/10.1001/jamaneurol.2019.1424CrossRefPubMedCentralPubMed

58.

Hansra GK, Popov G, Banaczek PO, Vogiatzis M, Jegathees T, Goldbury CS et al (2019) The neuritic plaque in Alzheimer’s disease: perivascular degeneration of neuronal processes. Neurobiol Aging 82:88–101. https://doi.org/10.1016/j.neurobiolaging.2019.06.009CrossRefPubMed

59.

Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256:184–185. https://doi.org/10.1126/science.1566067CrossRefPubMed

60.

Harkany T, Abrahám I, Timmerman W, Laskay G, Tóth B, Sasvári M et al (2000) beta-amyloid neurotoxicity is mediated by a glutamate-triggered excitotoxic cascade in rat nucleus basalis. Eur J Neurosci 12:2735–2745. https://doi.org/10.1046/j.1460-9568.2000.00164.xCrossRefPubMed

61.

Hase Y, Ding R, Harrison G, Hawthorne E, King A, Gettings S et al (2019) White matter capillaries in vascular and neurodegenerative dementias. Acta Neuropathol Commun 7:16. https://doi.org/10.1186/s40478-019-0666-xCrossRefPubMedPubMedCentral

62.

He Z, Guo JL, McBride JD, Narasimhan S, Kim H, Changolkar L et al (2018) Amyloid-β plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat Med 24:29–38. https://doi.org/10.1038/nm.4443CrossRefPubMed

63.

Hijazi S, Heistek TS, Scheltens P, Neumann U, Shimshek DR, Mansvelder HD et al (2019) Early restoration of parvalbumin interneuron activity prevents memory loss and network hyperexcitability in a mouse model of Alzheimer’s disease. Mol Psychiatry. https://doi.org/10.1038/s41380-019-0483-4. (Online ahead of print)CrossRefPubMedPubMedCentral

64.

Hilal-Dandan R, Villegas S, Gonzalez A, Brunton LL (1997) The quasi-irreversible nature of endothelin binding and G protein-linked signaling in cardiac myocytes. J Pharmacol Exp Ther 281:267–273. https://jpet.aspetjournals.org/content/jpet/281/1/267.full.pdf. Accessed 20 Aug 2020

65.

Hill RA, Tong L, Yuan P, Murikinati S, Gupta S, Grutzendler J (2015) Regional blood flow in the normal and ischemic brain is controlled by arteriolar smooth muscle cell contractility and not by capillary pericytes. Neuron 87:95–110. https://doi.org/10.1016/j.neuron.2015.06.001CrossRefPubMedPubMedCentral

66.

Hladky SB, Barrand MA (2018) Elimination of substances from the brain parenchyma: efflux via perivascular pathways and via the blood-brain barrier. Fluids Barriers CNS 15:30. https://doi.org/10.1186/s12987-018-0113-6CrossRefPubMedPubMedCentral

67.

Hoover BR, Reed MN, Su J, Penrod RD, Kotilinek LA, Grant MK et al (2010) Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron 68:1067–1081. https://doi.org/10.1016/j.neuron.2010.11.030CrossRefPubMedPubMedCentral

68.

Howard R, Liu KY (2020) Questions EMERGE as Biogen claims aducanumab turnaround. Nat Rev Neurol 16:63–64. https://doi.org/10.1038/s41582-019-0295-9CrossRefPubMed

69.

Hughes TM, Craft S, Lopez OL (2015) Review of ‘the potential role of arterial stiffness in the pathogenesis of Alzheimer’s disease’. Neurodegener Dis Manag 5:121–135. https://doi.org/10.2217/nmt.14.53CrossRefPubMed

70.

Iaccarino HF, Singer AC, Martorell AJ, Rudenko A, Gao F, Gillingham TZ et al (2016) Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature 540:230–235. https://doi.org/10.1038/nature20587CrossRefPubMedPubMedCentral

71.

Iadecola C (2004) Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci 5:347–360. https://doi.org/10.1038/nrn1387CrossRefPubMed

72.

Iadecola C, Gottesman RF (2019) Neurovascular and cognitive dysfunction in hypertension. Circ Res 124:1025–1044. https://doi.org/10.1161/CIRCRESAHA.118.313260CrossRefPubMedPubMedCentral

73.

Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA et al (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med 4:147ra111. https://doi.org/10.1126/scitranslmed.3003748CrossRefPubMedPubMedCentral

74.

Iliff JJ, Wang M, Zeppenfeld DM, Venkataraman A, Plog BA, Liao Y et al (2013) Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain. J Neurosci 33:18190–18199. https://doi.org/10.1523/JNEUROSCI.1592-13.2013CrossRefPubMedPubMedCentral

75.

Ito S, Ueno T, Ohtsuki S, Terasaki T (2010) Lack of brain-to-blood efflux transport activity of low-density lipoprotein receptor-related protein-1 (LRP-1) for amyloid-beta peptide(1–40) in mouse: involvement of an LRP-1-independent pathway. J Neurochem 113:1356–1363. https://doi.org/10.1111/j.1471-4159.2010.06708.xCrossRefPubMed

76.

Iturria-Medina Y, Sotero RC, Toussaint PJ, Mateos-Pérez JM, Evans AC, Alzheimer’s Disease Neuroimaging Initiative (2016) Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis. Nat Commun 7:11934. https://doi.org/10.1038/ncomms11934CrossRefPubMedPubMedCentral

77.

Ji F, Pasternak O, Ng KK, Chong JSX, Liu S, Zhang L et al (2019) White matter microstructural abnormalities and default network degeneration are associated with early memory deficit in Alzheimer’s disease continuum. Sci Rep 9:4749. https://doi.org/10.1038/s41598-019-41363-2CrossRefPubMedPubMedCentral

78.

Johnston JA, Liu WW, Todd SA, Coulson DT, Murphy S, Irvine GB et al (2005) Expression and activity of beta-site amyloid precursor protein cleaving enzyme in Alzheimer’s disease. Biochem Soc Trans 33:1096–1100. https://doi.org/10.1042/bst20051096CrossRefPubMed

79.

Kanekiyo T, Cirrito JR, Liu C-C, Shinohara M, Li J, Schuler DR et al (2013) Neuronal clearance of amyloid-β by endocytic receptor LRP1. J Neurosci 33:19276–19283CrossRefPubMedPubMedCentral

80.

Kawamura J, Meyer JS, Terayama Y, Weathers S (1991) Cerebral white matter perfusion in dementia of Alzheimer type. Alzheimer Dis Assoc Disord 5:231–239. https://doi.org/10.1097/00002093-199100540-00002CrossRefPubMed

81.

Kennedy AM, Frackowiak RS, Newman SK, Bloomfield PM, Seaward J, Roques P et al (1995) Deficits in cerebral glucose metabolism demonstrated by positron emission tomography in individuals at risk of familial Alzheimer’s disease. Neurosci Lett 186:17–20. https://doi.org/10.1016/0304-3940(95)11270-7CrossRefPubMed

82.

Khennouf L, Gesslein B, Brazhe A, Octeau JC, Kutuzov N, Khakh BS et al (2018) Active role of capillary pericytes during stimulation-induced activity and spreading depolarization. Brain 141:2032–2046. https://doi.org/10.1093/brain/awy143CrossRefPubMedPubMedCentral

83.

Kimura T, Hashimura T, Miyakawa T (1991) Observations of microvessels in the brain with Alzheimer’s disease by the scanning electron microscopy. Jpn J Psychiatry Neurol 45:671–676. https://doi.org/10.1111/j.1440-1819.1991.tb01189.xCrossRefPubMed

84.

Kisler K, Nelson AR, Rege SV, Ramanathan A, Wang Y, Ahuja A et al (2017) Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain. Nat Neurosci 20:406–416. https://doi.org/10.1038/nn.4489CrossRefPubMedPubMedCentral

85.

Kleinberger G, Brendel M, Mracsko E, Wefers B, Groeneweg L, Xiang X et al (2017) The FTD-like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism. EMBO J 36:1837–1853. https://doi.org/10.15252/embj.201796516CrossRefPubMedPubMedCentral

86.

Koronyo-Hamaoui M, Koronyo Y, Ljubimov AV, Miller CA, Ko MK, Black KL et al (2011) Identification of amyloid plaques in retinas from Alzheimer’s patients and noninvasive in vivo optical imaging of retinal plaques in a mouse model. Neuroimage 54(Suppl 1):S204–217. https://doi.org/10.1016/j.neuroimage.2010.06.020CrossRefPubMed

87.

Krogh A (1920) Nobel Lecture. www.nobelprize.org/prizes/medicine/1920/krogh/lecture/.

88.

Kwon S, Moreno-Gonzalez I, Taylor-Presse K, Edwards Iii G, Gamez N, Calderon O et al (2019) Impaired peripheral lymphatic function and cerebrospinal fluid outflow in a mouse model of Alzheimer’s disease. J Alzheimers Dis 69:585–593. https://doi.org/10.3233/jad-190013CrossRefPubMedPubMedCentral

89.

Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M et al (1998) Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci, USA 95:6448–6453. https://doi.org/10.1073/pnas.95.11.6448CrossRefPubMedPubMedCentral

90.

Law CSW, Yeong KY (2020) Repurposing antihypertensive drugs for the management of Alzheimer’s disease. Curr Med Chem 27:1–15. https://doi.org/10.2174/0929867327666200312114223CrossRef

91.

Lee M-S, Tsai L-H (2003) Cdk5: one of the links between senile plaques and neurofibrillary tangles? J Alzheimers Dis 5:127–137. https://doi.org/10.3233/jad-2003-5207CrossRefPubMed

92.

Lei M, Xu H, Li Z, Wang Z, O’Malley TT, Zhang D et al (2016) Soluble Aβ oligomers impair hippocampal LTP by disrupting glutamatergic/GABAergic balance. Neurobiol Dis 85:111–121. https://doi.org/10.1016/j.nbd.2015.10.019CrossRefPubMed

93.

Li R-R, He Y-S, Liu M, Nie Z-Y, Huang L-H, Lu Z et al (2019) Analysis of correlation between cerebral perfusion and KIM score of white matter lesions in patients with Alzheimer’s disease. Neuropsychiatr Dis Treat 15:2705–2714. https://doi.org/10.2147/ndt.s207069CrossRefPubMedPubMedCentral

94.

Li S, Hong S, Shepardson NE, Walsh DM, Shankar GM, Selkoe D (2009) Soluble oligomers of amyloid beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron 62:788–801. https://doi.org/10.1016/j.neuron.2009.05.012CrossRefPubMedPubMedCentral

95.

Yanjun Li, Yongming Li, Li X, Zhang S, Zhao J, Zhu X et al (2017) Head injury as a risk factor for dementia and Alzheimer’s disease: a systematic review and meta-analysis of 32 observational studies. PLoS ONE 12:e0169650. https://doi.org/10.1371/journal.pone.0169650CrossRef

96.

Liu C-C, Hu J, Zhao N, Wang J, Wang N, Cirrito JR et al (2017) Astrocytic LRP1 mediates brain Aβ clearance and impacts amyloid deposition. J Neurosci 37:4023–4031. https://doi.org/10.1523/jneurosci.3442-16.2017CrossRefPubMedPubMedCentral

97.

Liu Q, Radwanski R, Babadjouni R, Patel A, Hodis DM, Baumbacher P et al (2019) Experimental chronic cerebral hypoperfusion results in decreased pericyte coverage and increased blood-brain barrier permeability in the corpus callosum. J Cereb Blood Flow Metab 39:240–250. https://doi.org/10.1177/0271678x17743670CrossRefPubMed

98.

Liu S-L, Wang C, Jiang T, Tan L, Xing A, Yu J-T (2016) The role of Cdk5 in Alzheimer’s disease. Mol Neurobiol 53:4328–4342. https://doi.org/10.1007/s12035-015-9369-xCrossRefPubMed

99.

Long JM, Holtzman DM (2019) Alzheimer disease: an update on pathobiology and treatment strategies. Cell 179:312–339. https://doi.org/10.1016/j.cell.2019.09.001CrossRefPubMedPubMedCentral

100.

Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD et al (2015) Structural and functional features of central nervous system lymphatic vessels. Nature 523:337–341. https://doi.org/10.1038/nature14432CrossRefPubMedPubMedCentral

101.

Love S, Miners JS (2017) Small vessel disease, neurovascular regulation and cognitive impairment: post-mortem studies reveal a complex relationship, still poorly understood. Clin Sci 131:1579–1589. https://doi.org/10.1042/cs20170148CrossRef

102.

Lovell MA, Abner E, Kryskio R, Xu L, Fister SX, Lynn BC (2015) Calcium channel blockers, progression to dementia, and effects on amyloid beta peptide production. Oxid Med Cell Longev 2015:787805. https://doi.org/10.1155/2015/787805CrossRefPubMedPubMedCentral

103.

Ma Q, Ineichen BV, Detmar M, Proulx ST (2017) Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice. Nat Commun 8:1434. https://doi.org/10.1038/s41467-017-01484-6CrossRefPubMedPubMedCentral

104.

Madry C, Kyrargyri V, Arancibia-Cárcamo IL, Jolivet R, Kohsaka S, Bryan RM et al (2018) Microglial ramification, surveillance, and interleukin-1β release are regulated by the two-pore domain K⁺ channel THIK-1. Neuron 97:299–312. https://doi.org/10.1016/j.neuron.2017.12.002CrossRefPubMedPubMedCentral

105.

Marshall RS, Lazar RM, Pile-Spellman J, Young WL, Duong DH, Joshi S et al (2001) Recovery of brain function during induced cerebral hypoperfusion. Brain 124:1208–1217. https://doi.org/10.1093/brain/124.6.1208CrossRefPubMed

106.

Masuda T, Croom D, Hida H, Kirov SA (2011) Capillary blood flow around microglial somata determines dynamics of microglial processes in ischemic conditions. Glia 59:1744–1753. https://doi.org/10.1002/glia.21220CrossRefPubMedPubMedCentral

107.

Mattsson N, Tosun D, Insel PS, Simonson A, Jack CR, Beckett LA et al (2014) Association of brain amyloid-β with cerebral perfusion and structure in Alzheimer’s disease and mild cognitive impairment. Brain 137:1550–1561. https://doi.org/10.1093/brain/awu043CrossRefPubMedPubMedCentral

108.

Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC et al (2010) Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science 330:1774. https://doi.org/10.1126/science.1197623CrossRefPubMedPubMedCentral

109.

Mehta D, Jackson R, Paul G, Shi J, Sabbagh M (2017) Why do trials for Alzheimer’s disease drugs keep failing? A discontinued drug perspective for 2010–2015. Expert Opin Investig Drugs 26:735–739. https://doi.org/10.1080/13543784.2017.1323868CrossRefPubMedPubMedCentral

110.

Mehta JL, Nichols WW, Mehta P (1988) Neutrophils as potential participants in acute myocardial ischemia: relevance to reperfusion. J Am Coll Cardiol 11:1309–1316. https://doi.org/10.1016/0735-1097(88)90297-5CrossRefPubMed

111.

Michels L, Warnock G, Buck A, Macauda G, Leh SE, Kaelin AM et al (2016) Arterial spin labeling imaging reveals widespread and Aβ-independent reductions in cerebral blood flow in elderly apolipoprotein epsilon-4 carriers. J Cereb Blood Flow Metab 36:581–595. https://doi.org/10.1177/0271678x15605847CrossRefPubMed

112.

Mielke R, Herholz K, Grond M, Kessler J, Heiss WD (1994) Clinical deterioration in probable Alzheimer’s disease correlates with progressive metabolic impairment of association areas. Dementia 5:36–41. https://doi.org/10.1159/000106692CrossRefPubMed

113.

Minami M, Kimura M, Iwamoto N, Arai H (1995) Endothelin-1-like immunoreactivity in cerebral cortex of Alzheimer-type dementia. Prog Neuropsychopharmacol Biol Psychiatry 19:509–513. https://doi.org/10.1016/0278-5846(95)00031-pCrossRefPubMed

114.

Miners JS, Palmer JC, Love S (2016) Pathophysiology of hypoperfusion of the precuneus in early Alzheimer’s disease. Brain Pathol 26:533–541. https://doi.org/10.1111/bpa.12331CrossRefPubMed

115.

Minoshima S, Giordani B, Berent S, Frey KA, Foster NL, Kuhl DE (1997) Metabolic reduction in the posterior cingulate cortex in very early Alzheimer’s disease. Ann Neurol 42:85–94. https://doi.org/10.1002/ana.410420114CrossRefPubMed

116.

Mitew S, Kirkcaldie MTK, Halliday GM, Shepherd CE, Vickers JC, Dickson TC (2010) Focal demyelination in Alzheimer’s disease and transgenic mouse models. Acta Neuropathol 119:567–577. https://doi.org/10.1007/s00401-010-0657-2CrossRefPubMed

117.

Mok VCT, Lam BYK, Wong A, Ko H, Markus HS, Wong LKS (2017) Early-onset and delayed-onset poststroke dementia—revisiting the mechanisms. Nat Rev Neurol 13:148–159. https://doi.org/10.1038/nrneurol.2017.16CrossRefPubMed

118.

Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP, Zhao Z et al (2015) Blood-brain barrier breakdown in the aging human hippocampus. Neuron 85:296–302. https://doi.org/10.1016/j.neuron.2014.12.032CrossRefPubMedPubMedCentral

119.

Montagne A, Nation DA, Sagare AP, Barisano G, Sweeney MD, Chakhoyan A et al (2020) APOE4 leads to blood–brain barrier dysfunction predicting cognitive decline. Nature 581:71–76. https://doi.org/10.1038/s41586-020-2247-3CrossRefPubMedPubMedCentral

120.

Morizawa YM, Hirayama Y, Ohno N, Shibata S, Shigetomi E, Sui Y et al (2017) Reactive astrocytes function as phagocytes after brain ischemia via ABCA1-mediated pathway. Nat Commun 8:28. https://doi.org/10.1038/s41467-017-00037-1CrossRefPubMedPubMedCentral

121.

Morrison HW, Filosa JA (2013) A quantitative spatiotemporal analysis of microglia morphology during ischemic stroke and reperfusion. J Neuroinflammation 10:4. https://doi.org/10.1186/1742-2094-10-4CrossRefPubMedPubMedCentral

122.

Mottet D, Dumont V, Deccache Y, Demazy C, Ninane N, Raes M et al (2003) Regulation of hypoxia-inducible factor-1alpha protein level during hypoxic conditions by the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3beta pathway in HepG2 cells. J Biol Chem 278:31277–31285. https://doi.org/10.1074/jbc.M300763200CrossRefPubMed

123.

Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G et al (2000) High-level neuronal expression of abeta 1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 20:4050–4058. https://doi.org/10.1523/jneurosci.20-11-04050.2000CrossRefPubMedPubMedCentral

124.

Muller M, van der Graaf Y, Visseren FL, Mali WP, Geerlings MI, SMART Study Group (2012) Hypertension and longitudinal changes in cerebral blood flow: the SMART-MR study. Ann Neurol 71:825–833. https://doi.org/10.1002/ana.23554CrossRefPubMed

125.

Murray KN, Girard S, Holmes WM, Parkes LM, Williams SR, Parry-Jones AR et al (2014) Systemic inflammation impairs tissue reperfusion through endothelin-dependent mechanisms in cerebral ischemia. Stroke 45:3412–3419. https://doi.org/10.1161/strokeaha.114.006613CrossRefPubMedPubMedCentral

126.

Nation DA, Sweeney MD, Montagne A, Sagare AP, D’Orazio LM, Pachicano M et al (2019) Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat Med 25:270–276. https://doi.org/10.1038/s41591-018-0297-yCrossRefPubMedPubMedCentral

127.

Nelson AR, Sagare MA, Wang Y, Kisler K, Zhao Z, Zlokovic BV (2020) Channelrhodopsin excitation contracts brain pericytes and reduces blood flow in the aging mouse brain in vivo. Front Aging Neurosci 12:108. https://doi.org/10.3389/fnagi.2020.00108CrossRefPubMedPubMedCentral

128.

Nielsen RB, Egefjord L, Angleys H, Mouridsen K, Gejl M, Møller A et al (2017) Capillary dysfunction is associated with symptom severity and neurodegeneration in Alzheimer’s disease. Alzheimers Dement 13:1143–1153. https://doi.org/10.1016/j.jalz.2017.02.007CrossRefPubMed

129.

Niwa K, Kazama K, Younkin SG, Carlson GA, Iadecola C (2002) Alterations in cerebral blood flow and glucose utilization in mice overexpressing the amyloid precursor protein. Neurobiol Dis 9:61–68. https://doi.org/10.1006/nbdi.2001.0460CrossRefPubMed

130.

Niwa K, Porter VA, Kazama K, Cornfield D, Carlson GA, Iadecola C (2001) A beta-peptides enhance vasoconstriction in cerebral circulation. Am J Physiol Heart Circ Physiol 281:H2417–2424. https://doi.org/10.1152/ajpheart.2001.281.6.H2417CrossRefPubMed

131.

Niwa K, Younkin L, Ebeling C, Turner SK, Westaway D, Younkin S et al (2000) Abeta 1–40-related reduction in functional hyperemia in mouse neocortex during somatosensory activation. Proc Natl Acad Sci USA 97:9735–9740. https://doi.org/10.1073/pnas.97.17.9735CrossRefPubMedPubMedCentral

132.

Norman KE, Cotter MJ, Stewart JB, Abbitt KB, Ali M, Wagner BE et al (2003) Combined anticoagulant and antiselectin treatments prevent lethal intravascular coagulation. Blood 101:921–928. https://doi.org/10.1182/blood-2001-12-0190CrossRefPubMed

133.

Nortley R, Korte N, Izquierdo P, Hirunpattarasilp C, Mishra A, Jaunmuktane Z et al (2019) Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes. Science. https://doi.org/10.1126/science.aav9518CrossRefPubMedPubMedCentral

134.

Ortner M, Hauser C, Schmaderer C, Muggenthaler C, Hapfelmeier A, Sorg C et al (2019) Decreased vascular pulsatility in Alzheimer’s disease dementia measured by transcranial color-coded duplex sonography. Neuropsychiatr Dis Treat 15:3487–3499. https://doi.org/10.2147/ndt.s225754CrossRefPubMedPubMedCentral

135.

Palmer JC, Barker R, Kehoe PG, Love S (2012) Endothelin-1 is elevated in Alzheimer’s disease and upregulated by amyloid-β. J Alzheimers Dis 29:853–861. https://doi.org/10.3233/JAD-2012-111760CrossRefPubMed

136.

Panza F, Lozupone M, Seripa D, Imbimbo BP (2019) Amyloid-β immunotherapy for alzheimer disease: is it now a long shot? Ann Neurol 85:303–315. https://doi.org/10.1002/ana.25410CrossRefPubMed

137.

Pappolla M, Sambamurti K, Vidal R, Pacheco-Quinto J, Poeggeler B, Matsubara E (2014) Evidence for lymphatic Aβ clearance in Alzheimer’s transgenic mice. Neurobiol Dis 71:215–219. https://doi.org/10.1016/j.nbd.2014.07.012CrossRefPubMedPubMedCentral

138.

Parhizkar S, Arzberger T, Brendel M, Kleinberger G, Deussing M, Focke C et al (2019) Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat Neurosci 22:191–204. https://doi.org/10.1038/s41593-018-0296-9CrossRefPubMedPubMedCentral

139.

Paris D, Quadros A, Humphrey J, Patel N, Crescentini R, Crawford F et al (2004) Nilvadipine antagonizes both Abeta vasoactivity in isolated arteries, and the reduced cerebral blood flow in APPsw transgenic mice. Brain Res 999:53–61. https://doi.org/10.1016/j.brainres.2003.11.061CrossRefPubMed

140.

Park J-H, Hong J-H, Lee S-W, Ji HD, Jung J-A, Yoon K-W et al (2019) The effect of chronic cerebral hypoperfusion on the pathology of Alzheimer’s disease: a positron emission tomography study in rats. Sci Rep 9:14102. https://doi.org/10.1038/s41598-019-50681-4CrossRefPubMedPubMedCentral

141.

Park L, Uekawa K, Garcia-Bonilla L, Koizumi K, Murphy M, Pistik R et al (2017) Brain perivascular macrophages initiate the neurovascular dysfunction of Alzheimer Aβ peptides. Circ Res 121:258–269. https://doi.org/10.1161/CIRCRESAHA.117.311054CrossRefPubMedPubMedCentral

142.

Peng W, Achariyar TM, Li B, Liao Y, Mestre H, Hitomi E et al (2016) Suppression of glymphatic fluid transport in a mouse model of Alzheimer’s disease. Neurobiol Dis 93:215–225. https://doi.org/10.1016/j.nbd.2016.05.015CrossRefPubMedPubMedCentral

143.

Peppiatt CM, Howarth C, Mobbs P, Attwell D (2006) Bidirectional control of CNS capillary diameter by pericytes. Nature 443:700–704. https://doi.org/10.1038/nature05193CrossRefPubMedPubMedCentral

144.

Prohovnik I, Mayeux R, Sackeim HA, Smith G, Stern Y, Alderson PO (1988) Cerebral perfusion as a diagnostic marker of early Alzheimer’s disease. Neurology 38:931–937. https://doi.org/10.1212/wnl.38.6.931CrossRefPubMed

145.

Qiu L, Ng G, Tan EK, Liao P, Kandiah N, Zeng L (2016) Chronic cerebral hypoperfusion enhances Tau hyperphosphorylation and reduces autophagy in Alzheimer’s disease mice. Sci Rep 6:23964. https://doi.org/10.1038/srep23964CrossRefPubMedPubMedCentral

146.

Querques G, Borrelli E, Sacconi R, De Vitis L, Leocani L, Santangelo R et al (2019) Functional and morphological changes of the retinal vessels in Alzheimer’s disease and mild cognitive impairment. Sci Rep 9:63. https://doi.org/10.1038/s41598-018-37271-6CrossRefPubMedPubMedCentral

147.

Raz L, Bhaskar K, Weaver J, Marini S, Zhang Q, Thompson JF et al (2019) Hypoxia promotes tau hyperphosphorylation with associated neuropathology in vascular dysfunction. Neurobiol Dis 126:124–136. https://doi.org/10.1016/j.nbd.2018.07.009CrossRefPubMed

148.

Reiman EM, Caselli RJ, Yun LS, Chen K, Bandy D, Minoshima S et al (1996) Preclinical evidence of Alzheimer’s disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. N Engl J Med 334:752–758. https://doi.org/10.1056/NEJM199603213341202CrossRefPubMed

149.

Roh M-S, Eom T-Y, Zmijewska AA, De Sarno P, Roth KA, Jope RS (2005) Hypoxia activates glycogen synthase kinase-3 in mouse brain in vivo: protection by mood stabilizers and imipramine. Biol Psychiatry 57:278–286. https://doi.org/10.1016/j.biopsych.2004.10.039CrossRefPubMed

150.

Rudinskiy N, Grishchuk Y, Vaslin A, Puyal J, Delacourte A, Hirling H et al (2009) Calpain hydrolysis of alpha- and beta2-adaptins decreases clathrin-dependent endocytosis and may promote neurodegeneration. J Biol Chem 284:12447–12458. https://doi.org/10.1074/jbc.m804740200CrossRefPubMedPubMedCentral

151.

Ruitenberg A, den Heijer T, Bakker SLM, van Swieten JC, Koudstaal PJ, Hofman A et al (2005) Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam Study. Ann Neurol 57:789–794. https://doi.org/10.1002/ana.20493CrossRefPubMed

152.

Rungta RL, Chaigneau E, Osmanski B-F, Charpak S (2018) Vascular compartmentalization of functional hyperemia from the synapse to the pia. Neuron 99:362–375. https://doi.org/10.1016/j.neuron.2018.06.012CrossRefPubMedPubMedCentral

153.

Sagare AP, Bell RD, Zhao Z, Ma Q, Winkler EA, Ramanathan A et al (2013) Pericyte loss influences Alzheimer-like neurodegeneration in mice. Nat Commun 4:2932. https://doi.org/10.1038/ncomms3932CrossRefPubMed

154.

Sahathevan R, Linden T, Villemagne VL, Churilov L, Ly JV, Rowe C et al (2016) Positron emission tomographic imaging in stroke: cross-sectional and follow-up assessment of amyloid in ischemic stroke. Stroke 47:113–119. https://doi.org/10.1161/strokeaha.115.010528CrossRefPubMed

155.

Sandsmark DK, Bashir A, Wellington CL, Diaz-Arrastia R (2019) Cerebral microvascular injury: a potentially treatable endophenotype of traumatic brain injury-induced neurodegeneration. Neuron 103:367–379. https://doi.org/10.1016/j.neuron.2019.06.002CrossRefPubMedPubMedCentral

156.

Schley D, Carare-Nnadi R, Please CP, Perry VH, Weller RO (2006) Mechanisms to explain the reverse perivascular transport of solutes out of the brain. J Theor Biol 238:962–974. https://doi.org/10.1016/j.jtbi.2005.07.005CrossRefPubMed

157.

Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791. https://doi.org/10.1126/science.1074069CrossRefPubMed

158.

Seo J, Kritskiy O, Watson LA, Barker SJ, Dey D, Raja WK et al (2017) Inhibition of p25/Cdk5 attenuates tauopathy in mouse and iPSC models of frontotemporal dementia. J Neurosci 37:9917–9924. https://doi.org/10.1523/JNEUROSCI.0621-17.2017CrossRefPubMedPubMedCentral

159.

Shager B, Brown CE (2020) Susceptibility to capillary plugging can predict brain region specific vessel loss with aging. J Cereb Blood Flow Metab. https://doi.org/10.1177/0271678x19895245. (Epub ahead of print)CrossRef

160.

Shibata M, Yamada S, Kumar SR, Calero M, Bading J, Frangione B et al (2000) Clearance of Alzheimer’s amyloid-ss(1–40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest 106:1489–1499. https://doi.org/10.1172/jci10498CrossRefPubMedPubMedCentral

161.

Shinohara M, Tachibana M, Kanekiyo T, Bu G (2017) Role of LRP1 in the pathogenesis of Alzheimer’s disease: evidence from clinical and preclinical studies. J Lipid Res 58:1267–1281. https://doi.org/10.1194/jlr.r075796CrossRefPubMedPubMedCentral

162.

Small GW, Ercoli LM, Silverman DH, Huang SC, Komo S, Bookheimer SY et al (2000) Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer’s disease. Proc Natl Acad Sci USA 97:6037–6042. https://doi.org/10.1073/pnas.090106797CrossRefPubMedPubMedCentral

163.

Small GW, Mazziotta JC, Collins MT, Baxter LR, Phelps ME, Mandelkern MA et al (1995) Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease. JAMA 273:942–947. https://doi.org/10.1001/jama.1995.03520360056039CrossRefPubMed

164.

Smith AJ, Verkman AS (2018) The “glymphatic” mechanism for solute clearance in Alzheimer’s disease: game changer or unproven speculation? FASEB J 32:543–551. https://doi.org/10.1096/fj.201700999CrossRefPubMed

165.

Smith GS, de Leon MJ, George AE, Kluger A, Volkow ND, McRae T et al (1992) Topography of cross-sectional and longitudinal glucose metabolic deficits in Alzheimer’s disease. Pathophysiologic implications. Arch Neurol 49:1142–1150. https://doi.org/10.1001/archneur.1992.00530350056020CrossRefPubMed

166.

Špiranec K, Chen W, Werner F, Nikolaev VO, Naruke T, Koch F et al (2018) Endothelial C-type natriuretic peptide acts on pericytes to regulate microcirculatory flow and blood pressure. Circulation 138:494–508. https://doi.org/10.1161/circulationaha.117.033383CrossRefPubMed

167.

Storck SE, Meister S, Nahrath J, Meißner JN, Schubert N, Spiezio A et al (2016) Endothelial LRP1 transports amyloid-β(1–42) across the blood-brain barrier. J Clin Invest 126:123–136. https://doi.org/10.1172/jci81108CrossRefPubMed

168.

Sun X, He G, Qing H, Zhou W, Dobie F, Cai F et al (2006) Hypoxia facilitates Alzheimer’s disease pathogenesis by up-regulating BACE1 gene expression. Proc Natl Acad Sci USA 103:18727–18732. https://doi.org/10.1073/pnas.0606298103CrossRefPubMedPubMedCentral

169.

Suo Z, Humphrey J, Kundtz A, Sethi F, Placzek A, Crawford F et al (1998) Soluble Alzheimer’s beta-amyloid constricts the cerebral vasculature in vivo. Neurosci Lett 257:77–80. https://doi.org/10.1016/s0304-3940(98)00814-3CrossRefPubMed

170.

Takahashi R, Ishii K, Shimada K, Ohkawa S, Nishimura Y (2010) Hypoperfusion of the motor cortex associated with parkinsonism in dementia with Lewy bodies. J Neurol Sci 288:88–91. https://doi.org/10.1016/j.jns.2009.09.033CrossRefPubMed

171.

Tesco G, Koh YH, Kang EL, Cameron AN, Das S, Sena-Esteves M et al (2007) Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity. Neuron 54:721–737. https://doi.org/10.1016/j.neuron.2007.05.012CrossRefPubMedPubMedCentral

172.

Thambisetty M, Beason-Held L, An Y, Kraut MA, Resnick SM (2010) APOE epsilon4 genotype and longitudinal changes in cerebral blood flow in normal aging. Arch Neurol 67:93–98. https://doi.org/10.1001/archneurol.2009.913CrossRefPubMedPubMedCentral

173.

Thiebault AM, Hedou E, Marciniak SJ, Vivien D, Roussel BD (2019) Proteostasis during cerebral ischemia. Front Neurosci 13:637. https://doi.org/10.3389/fnins.2019.00637CrossRef

174.

Tong X-K, Lecrux C, Rosa-Neto P, Hamel E (2012) Age-dependent rescue by simvastatin of Alzheimer’s disease cerebrovascular and memory deficits. J Neurosci 32:4705–4715. https://doi.org/10.1523/JNEUROSCI.0169-12.2012CrossRefPubMedPubMedCentral

175.

van Giersbergen PLM, Dingemanse J (2007) Effect of gender on the tolerability, safety and pharmacokinetics of clazosentan following long-term infusion. Clin Drug Investig 27:797–802. https://doi.org/10.2165/00044011-200727110-00006CrossRefPubMed

176.

Verret L, Mann EO, Hang GB, Barth AMI, Cobos I, Ho K et al (2012) Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model. Cell 149:708–721. https://doi.org/10.1016/j.cell.2012.02.046CrossRefPubMedPubMedCentral

177.

Wang X, Xing A, Xu C, Cai Q, Liu H, Li L (2010) Cerebrovascular hypoperfusion induces spatial memory impairment, synaptic changes, and amyloid-β oligomerization in rats. J Alzheimers Dis 21:813–822. https://doi.org/10.3233/JAD-2010-100216CrossRefPubMed

178.

Wang Y, Nelson LD, LaRoche AA, Pfaller AY, Nencka AS, Koch KM et al (2016) Cerebral blood flow alterations in acute sport-related concussion. J Neurotrauma 33:1227–1236. https://doi.org/10.1089/neu.2015.4072CrossRefPubMedPubMedCentral

179.

Weller RO, Subash M, Preston SD, Mazanti I, Carare RO (2008) Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer's disease. Brain Pathol 18:253–266. https://doi.org/10.1111/j.1750-3639.2008.00133.xCrossRefPubMed

180.

Wierenga CE, Hays CC, Zlatar ZZ (2014) Cerebral blood flow measured by arterial spin labeling MRI as a preclinical marker of Alzheimer’s disease. J Alzheimers Dis 42(Suppl 4):S411–419. https://doi.org/10.3233/JAD-141467CrossRefPubMedPubMedCentral

181.

Wilhelmus MM, Otte-Höller I, van Triel JJ, Veerhuis R, Maat-Schieman ML, Bu G et al (2007) Lipoprotein receptor-related protein-1 mediates amyloid-beta-mediated cell death of cerebrovascular cells. Am J Pathol 171:1989–1999. https://doi.org/10.2353/ajpath.2007.070050CrossRefPubMedPubMedCentral

182.

Wingo AP, Fan W, Duong DM, Gerasimov ES, Dammer EB, Liu Y et al (2020) Shared proteomic effects of cerebral atherosclerosis and Alzheimer’s disease on the human brain. Nat Neurosci 23:696–700. https://doi.org/10.1038/s41593-020-0635-5CrossRefPubMedPubMedCentral

183.

Wu C-L, Wen S-H (2016) A 10-year follow-up study of the association between calcium channel blocker use and the risk of dementia in elderly hypertensive patients. Medicine 95:e4593. https://doi.org/10.1097/md.0000000000004593CrossRefPubMedPubMedCentral

184.

Xiong M, Zhang T, Zhang L-M, Lu S-D, Huang Y-L, Sun F-Y (2008) Caspase inhibition attenuates accumulation of beta-amyloid by reducing beta-secretase production and activity in rat brains after stroke. Neurobiol Dis 32:433–441. https://doi.org/10.1016/j.nbd.2008.08.007CrossRefPubMed

185.

Yamada M, Hayashi H, Suzuki K, Sato S, Inoue D, Iwatani Y et al (2019) Furin-mediated cleavage of LRP1 and increase in ICD of LRP1 after cerebral ischemia and after exposure of cultured neurons to NMDA. Sci Rep 9:11782. https://doi.org/10.1038/s41598-019-48279-xCrossRefPubMedPubMedCentral

186.

Yang J, Lunde LK, Nuntagij P, Oguchi T, Camassa LMA, Nilsson LNG et al (2011) Loss of astrocyte polarization in the tg-ArcSwe mouse model of Alzheimer’s disease. J Alzheimers Dis 27:711–722. https://doi.org/10.3233/jad-2011-110725CrossRefPubMed

187.

Yemisci M, Gursoy-Ozdemir Y, Vural A, Can A, Topalkara K, Dalkara T (2009) Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery. Nat Med 15:1031–1037. https://doi.org/10.1038/nm.2022CrossRefPubMed

188.

Yew B, Nation DA, Alzheimer’s Disease Neuroimaging Initiative (2017) Cerebrovascular resistance: effects on cognitive decline, cortical atrophy, and progression to dementia. Brain 140:1987–2001. https://doi.org/10.1093/brain/awx112CrossRefPubMedPubMedCentral

189.

Yun C-H, Lee H-Y, Lee SK, Kim H, Seo HS, Bang SA et al (2017) Amyloid burden in obstructive sleep apnea. J Alzheimers Dis 59:21–29. https://doi.org/10.3233/JAD-161047CrossRefPubMed

190.

Zeisel A, Hochgerner H, Lönnerberg P, Johnsson A, Memic F, van der Zwan J et al (2018) Molecular architecture of the mouse nervous system. Cell 174:999–1014. https://doi.org/10.1016/j.cell.2018.06.021CrossRefPubMedPubMedCentral

191.

Zhai P, Sciarretta S, Galeotti J, Volpe M, Sadoshima J (2011) Differential roles of GSK-3β during myocardial ischemia and ischemia/reperfusion. Circ Res 109:502–511. https://doi.org/10.1161/CIRCRESAHA.111.249532CrossRefPubMedPubMedCentral

192.

Zhang C, Zhu Y, Wang S, Zachory WZ, Jiang MQ, Zhang Y et al (2018) Temporal gene expression profiles after focal cerebral ischemia in mice. Aging Dis 9:249–261. https://doi.org/10.14336/ad.2017.0424CrossRefPubMedPubMedCentral

193.

Zhang X, Yin X, Zhang J, Li A, Gong H, Luo Q et al (2019) High resolution mapping of brain vasculature and its impairment in the hippocampus of Alzheimer’s disease mice. Natl Sci Rev 6:1223–1238. https://doi.org/10.1093/nsr/nwz124CrossRefPubMedPubMedCentral

194.

Zhang Y, Xiong M, Yan R-Q, Sun F-Y (2010) Mutant ubiquitin-mediated beta-secretase stability via activation of caspase-3 is related to beta-amyloid accumulation in ischemic striatum in rats. J Cereb Blood Flow Metab 30:566–575. https://doi.org/10.1038/jcbfm.2009.228CrossRefPubMed

195.

Zhao Y, Wu X, Li X, Jiang L-L, Gui X, Liu Y et al (2018) TREM2 Is a receptor for β-amyloid that mediates microglial function. Neuron 97:1023–1031. https://doi.org/10.1016/j.neuron.2018.01.031CrossRefPubMedPubMedCentral

196.

Zhao Z, Sagare AP, Ma Q, Halliday MR, Kong P, Kisler K et al (2015) Central role for PICALM in amyloid-β blood-brain barrier transcytosis and clearance. Nat Neurosci 18:978–987. https://doi.org/10.1038/nn.4025CrossRefPubMedPubMedCentral

197.

Zhiyou C, Yong Y, Shanquan S, Jun Z, Liangguo H, Ling Y et al (2009) Upregulation of BACE1 and beta-amyloid protein mediated by chronic cerebral hypoperfusion contributes to cognitive impairment and pathogenesis of Alzheimer’s disease. Neurochem Res 34:1226–1235. https://doi.org/10.1007/s11064-008-9899-yCrossRefPubMed

198.

Zlokovic BV (2005) Neurovascular mechanisms of Alzheimer’s neurodegeneration. Trends Neurosci 28:202–208. https://doi.org/10.1016/j.tins.2005.02.001CrossRefPubMed

199.

Zott B, Simon MM, Hong W, Unger F, Chen-Engerer H-J, Frosch MP, Sakmann B et al (2019) A vicious cycle of β amyloid-dependent neuronal hyperactivation. Science 365:559–565. https://doi.org/10.1126/science.aay0198CrossRefPubMedPubMedCentral

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Cerebral blood flow decrease as an early pathological mechanism in Alzheimer's disease

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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