Review Article

Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders

  • Nature Reviews Neuroscience volume 12, pages 723738 (2011)
  • doi:10.1038/nrn3114
  • Download Citation
Published:

Abstract

The neurovascular unit (NVU) comprises brain endothelial cells, pericytes or vascular smooth muscle cells, glia and neurons. The NVU controls blood–brain barrier (BBB) permeability and cerebral blood flow, and maintains the chemical composition of the neuronal 'milieu', which is required for proper functioning of neuronal circuits. Recent evidence indicates that BBB dysfunction is associated with the accumulation of several vasculotoxic and neurotoxic molecules within brain parenchyma, a reduction in cerebral blood flow, and hypoxia. Together, these vascular-derived insults might initiate and/or contribute to neuronal degeneration. This article examines mechanisms of BBB dysfunction in neurodegenerative disorders, notably Alzheimer's disease, and highlights therapeutic opportunities relating to these neurovascular deficits.

  • Subscribe to Nature Reviews Neuroscience for full access:

    $265

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

References

  1. 1.

    The blood–brain barrier in health and chronic neurodegenerative disorders. Neuron 57, 178–201 (2008).

  2. 2.

    , & The science of stroke: mechanisms in search of treatments. Neuron 67, 181–198 (2010). A comprehensive review describing mechanisms of ischaemic injury to the neurovascular unit.

  3. 3.

    Neurovascular mechanisms of Alzheimer's neurodegeneration. Trends Neurosci. 28, 202–208 (2005).

  4. 4.

    & Review: cerebral microvascular pathology in ageing and neurodegeneration. Neuropathol. Appl. Neurobiol. 37, 56–74 (2011).

  5. 5.

    et al. Role of the MEOX2 homeobox gene in neurovascular dysfunction in Alzheimer disease. Nature Med. 11, 959–965 (2005). A study demonstrating that low expression of MEOX2 in brain endothelium leads to aberrant angiogenesis and vascular regression in Alzheimer's disease.

  6. 6.

    , & Fibrin deposition accelerates neurovascular damage and neuroinflammation in mouse models of Alzheimer's disease. J. Exp. Med. 204, 1999–2008 (2007). A study showing BBB breakdown in models of Alzheimer's disease.

  7. 7.

    et al. Microvascular injury and blood–brain barrier leakage in Alzheimer's disease. Neurobiol. Aging 28, 977–986 (2007).

  8. 8.

    et al. ALS-causing SOD1 mutants generate vascular changes prior to motor neuron degeneration. Nature Neurosci. 11, 420–422 (2008). A study demonstrating that BSCB defects precede motor neuron degeneration in mice that develop an ALS-like disease.

  9. 9.

    Vascular basis for brain degeneration: faltering controls and risk factors for dementia. Nutr. Rev. 68, S74–S87 (2010).

  10. 10.

    & Vascular risk factors: imaging and neuropathologic correlates. J. Alzheimers Dis. 20, 699–709 (2010).

  11. 11.

    et al. Disruption of neurovascular unit prior to motor neuron degeneration in amyotrophic lateral sclerosis. J. Neurosci. Res. 89, 718–728 (2011).

  12. 12.

    et al. Engaging neuroscience to advance translational research in brain barrier biology. Nature Rev. Neurosci. 12, 169–182 (2011).

  13. 13.

    & Dysfunctional cell–cell signaling in the neurovascular unit as a paradigm for central nervous system disease. Stroke 40, S4–S7 (2009).

  14. 14.

    Molecular biology of the blood–brain and the blood–cerebrospinal fluid barriers: similarities and differences. Fluids Barriers CNS 8, 3 (2011).

  15. 15.

    , , , & Na+-dependent glutamate transporters (EAAT1, EAAT2, and EAAT3) of the blood–brain barrier. A mechanism for glutamate removal. J. Biol. Chem. 274, 31891–31895 (1999).

  16. 16.

    Coupling of the NMDA receptor to neuroprotective and neurodestructive events. Biochem. Soc. Trans. 37, 1147–1160 (2009).

  17. 17.

    & ATP-binding cassette transporters and their roles in protecting the brain. Neuroscientist 17, 423–436 (2011).

  18. 18.

    , & Minireview: thyroid hormone transporters: the knowns and the unknowns. Mol. Endocrinol. 25, 1–14 (2011).

  19. 19.

    , & Blood–brain barrier permeability to leucine-enkephalin, D-alanine2-D-leucine5-enkephalin and their N-terminal amino acid (tyrosine). Brain Res. 336, 125–132 (1985).

  20. 20.

    , , , & Transport of leucine-enkephalin across the blood–brain barrier in the perfused guinea pig brain. J. Neurochem. 49, 310–315 (1987).

  21. 21.

    , , & Kinetic analysis of leucine–enkephalin cellular uptake at the luminal side of the blood–brain barrier of an in situ perfused guinea-pig brain. J. Neurochem. 53, 1333–1340 (1989).

  22. 22.

    et al. Kinetics of arginine-vasopressin uptake at the blood–brain barrier. Biochim. Biophys. Acta 1025, 191–198 (1990).

  23. 23.

    , , , & Permeability of the blood–cerebrospinal fluid and blood–brain barriers to thyrotropin-releasing hormone. Brain Res. 358, 191–199 (1985).

  24. 24.

    et al. Isolation of peptide transport system-6 from brain endothelial cells: therapeutic effects with antisense inhibition in Alzheimer and stroke models. J. Cereb. Blood Flow Metab. 29, 411–422 (2009).

  25. 25.

    Blood–brain barrier delivery. Drug Discov. Today 12, 54–61 (2007).

  26. 26.

    et al. Neuronal activity drives localized blood–brain-barrier transport of serum insulin-like growth factor-I into the CNS. Neuron 67, 834–846 (2010).

  27. 27.

    Blood–brain barrier as a regulatory interface. Forum Nutr. 63, 102–110 (2010).

  28. 28.

    et al. Endothelial protein C receptor-assisted transport of activated protein C across the mouse blood–brain barrier. J. Cereb. Blood Flow Metab. 29, 25–33 (2009).

  29. 29.

    Astrocytes take center stage in salt sensing. Neuron 54, 3–5 (2007).

  30. 30.

    et al. Glial Nax channels control lactate signaling to neurons for brain [Na+] sensing. Neuron 54, 59–72 (2007).

  31. 31.

    , , , & Decreased mRNA expression of tight junction proteins in lumbar spinal cords of patients with ALS. Neurology 72, 1614–1616 (2009).

  32. 32.

    , & Disruption of central nervous system barriers in multiple sclerosis. Biochim. Biophys. Acta 1812, 252–264 (2011).

  33. 33.

    et al. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 68, 409–427 (2010). A study showing that loss of pericytes leads to BBB breakdown and hypoperfusion, resulting in secondary neurodegenerative changes.

  34. 34.

    Matrix metalloproteinases and their multiple roles in neurodegenerative diseases. Lancet Neurol. 8, 205–216 (2009).

  35. 35.

    et al. Activated protein C inhibits tissue plasminogen activator-induced brain hemorrhage. Nature Med. 12, 1278–1285 (2006).

  36. 36.

    , , & Pericytes are required for blood–brain barrier integrity during embryogenesis. Nature 468, 562–566 (2010). A study showing that pericytes control the formation of the BBB during embryonic development.

  37. 37.

    et al. Endothelial Smad4 maintains cerebrovascular integrity by activating N-cadherin through cooperation with Notch. Dev. Cell 20, 291–302 (2011). A study showing that N-cadherin mediates pericyte–endothelial attachment in the cerebral blood vessels, preventing microhaemorrhages.

  38. 38.

    et al. Pericytes regulate the blood–brain barrier. Nature 468, 557–561 (2010). A study that reveals a role for pericytes in the maintenance of the BBB in vivo during adulthood.

  39. 39.

    & Expanding the definition of the blood–brain barrier to protein. Proc. Natl Acad. Sci. USA 78, 7820–7824 (1981).

  40. 40.

    et al. Thrombin, a mediator of neurotoxicity and memory impairment. Neurobiol. Aging 25, 783–793 (2004).

  41. 41.

    , , & Thrombin mediates severe neurovascular injury during ischemia. Stroke 41, 2348–2352 (2010).

  42. 42.

    & Neuronal death in the hippocampus is promoted by plasmin-catalyzed degradation of laminin. Cell 91, 917–925 (1997).

  43. 43.

    et al. Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells. J. Clin. Invest. 119, 3437–3449 (2009). A study showing that APC prevents BSCB breakdown, suppresses activation of microglia and protects motor neurons in ALS mice.

  44. 44.

    , , , & Brain oedema in focal ischaemia: molecular pathophysiology and theoretical implications. Lancet Neurol. 6, 258–268 (2007).

  45. 45.

    , , , & Chemical preconditioning-induced reactive astrocytosis contributes to the reduction of post-ischemic edema through aquaporin-4 downregulation. Exp. Neurol. 227, 89–95 (2011).

  46. 46.

    Neurovascular regulation in the normal brain and in Alzheimer's disease. Nature Rev. Neurosci. 5, 347–360 (2004).

  47. 47.

    , , & Bidirectional control of CNS capillary diameter by pericytes. Nature 443, 700–704 (2006). A study showing that pericytes control the diameter of brain capillaries in response to signals from neurons.

  48. 48.

    et al. Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery. Nature Med. 15, 1031–1037 (2009).

  49. 49.

    , , & Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science 323, 1211–1215 (2009).

  50. 50.

    , , , & Two-photon imaging of astrocytic Ca2+ signaling and the microvasculature in experimental mice models of Alzheimer's disease. Ann. NY Acad. Sci. 1097, 40–50 (2007).

  51. 51.

    et al. Altered brain activation in cognitively intact individuals at high risk for Alzheimer's disease. Neurology 53, 1391–1396 (1999).

  52. 52.

    et al. Patterns of brain activation in people at risk for Alzheimer's disease. N. Engl. J. Med. 343, 450–456 (2000).

  53. 53.

    et al. Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam Study. Ann. Neurol. 57, 789–794 (2005).

  54. 54.

    et al. APOE4 allele disrupts resting state fMRI connectivity in the absence of amyloid plaques or decreased CSF Aβ42. J. Neurosci. 30, 17035–17040 (2010).

  55. 55.

    et al. Cerebrovascular hypoperfusion induces spatial memory impairment, synaptic changes, and amyloid-β oligomerization in rats. J. Alzheimers Dis. 21, 813–822 (2010).

  56. 56.

    et al. Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535–539 (2002). A study showing that amyloid-β oligomers inhibit neuronal activity in the hipocampus.

  57. 57.

    , , & Oligemic hypoperfusion differentially affects tau and amyloid-β. Am. J. Pathol. 177, 300–310 (2010).

  58. 58.

    , , & Differential changes in phosphorylation of tau at PHF-1 and 12E8 epitopes during brain ischemia and reperfusion in gerbils. Neurochem. Res. 32, 729–737 (2007).

  59. 59.

    et al. Transgenic mice overexpressing APP and transforming growth factor-β1 feature cognitive and vascular hallmarks of Alzheimer's disease. Am. J. Pathol. 177, 3071–3080 (2010).

  60. 60.

    et al. Hypoxia facilitates Alzheimer's disease pathogenesis by up-regulating BACE1 gene expression. Proc. Natl Acad. Sci. USA 103, 18727–18732 (2006).

  61. 61.

    et al. Hypoxia-inducible factor 1α (HIF-1α)-mediated hypoxia increases BACE1 expression and β-amyloid generation. J. Biol. Chem. 282, 10873–10880 (2007).

  62. 62.

    et al. The up-regulation of BACE1 mediated by hypoxia and ischemic injury: role of oxidative stress and HIF1α. J. Neurochem. 108, 1045–1056 (2009).

  63. 63.

    et al. Hypoxia increases Aβ generation by altering β- and γ-cleavage of APP. Neurobiol. Aging 30, 1091–1098 (2009).

  64. 64.

    , , , & Acute hypoxia promote the phosphorylation of tau via ERK pathway. Neurosci. Lett. 474, 173–177 (2010).

  65. 65.

    et al. Hypoxia-induced down-regulation of neprilysin by histone modification in mouse primary cortical and hippocampal neurons. PLoS ONE 6, e19229 (2011).

  66. 66.

    et al. SRF and myocardin regulate LRP-mediated amyloid-β clearance in brain vascular cells. Nature Cell Biol. 11, 143–153 (2009). A study showing that hypoxia leads to a failure of LRP1-mediated amyloid-β clearance from brain arteries through an elevation in the levels of myocardin and serum response factor.

  67. 67.

    et al. Chemical hypoxia facilitates alternative splicing of EAAT2 in presymptomatic APP23 transgenic mice. Neurochem. Res. 33, 1005–1010 (2008).

  68. 68.

    , , , & Hypoxia suppresses astrocyte glutamate transport independently of amyloid formation. Biochem. Biophys. Res. Commun. 364, 100–104 (2007).

  69. 69.

    et al. Role of mitochondrial-mediated signaling pathways in Alzheimer disease and hypoxia. J. Bioenerg. Biomembr. 41, 433–440 (2009).

  70. 70.

    et al. Oxidative stress and altered mitochondrial function in neurodegenerative diseases: lessons from mouse models. CNS Neurol. Disord. Drug Targets 9, 439–454 (2010).

  71. 71.

    et al. Mitochondria: the missing link between preconditioning and neuroprotection. J. Alzheimers Dis. 20, S475–S485 (2010).

  72. 72.

    , , , & Mechanisms underlying inflammation in neurodegeneration. Cell 140, 918–934 (2010).

  73. 73.

    Neurovascular dysfunction, inflammation and endothelial activation: implications for the pathogenesis of Alzheimer's disease. J. Neuroinflammation 8, 26 (2011).

  74. 74.

    , & Microvessels from Alzheimer's disease brains kill neurons in vitro. Am. J. Pathol. 154, 337–342 (1999).

  75. 75.

    , & Cholinergic neurons degenerate when exposed to conditioned medium of primary rat brain capillary endothelial cells: counteraction by NGF, MK-801 and inflammation. Exp. Gerontol. 41, 609–618 (2006).

  76. 76.

    , , & Brain endothelial cells synthesize neurotoxic thrombin in Alzheimer's disease. Am. J. Pathol. 176, 1600–1606 (2010).

  77. 77.

    , , & Decreases in regional cerebral blood flow with normal aging. J. Cereb. Blood Flow Metab. 11, 684–689 (1991).

  78. 78.

    & Neurometabolic coupling in the lateral geniculate nucleus changes with extended age. J. Neurophysiol. 104, 414–425 (2010).

  79. 79.

    , , , & Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nature Genet. 39, 17–23 (2007).

  80. 80.

    , & The role of apolipoprotein E in Alzheimer's disease. Neuron 63, 287–303 (2009).

  81. 81.

    , & Apolipoprotein E in Alzheimer's disease and other neurological disorders. Lancet Neurol. 10, 241–252 (2011).

  82. 82.

    , , , & APOE ɛ4 genotype and longitudinal changes in cerebral blood flow in normal aging. Arch. Neurol. 67, 93–98 (2010).

  83. 83.

    & Blood–brain barrier: ageing and microvascular disease — systematic review and meta-analysis. Neurobiol. Aging 30, 337–352 (2009).

  84. 84.

    , , & Blood–brain barrier permeability is increased in normal-appearing white matter in patients with lacunar stroke and leucoaraiosis. J. Neurol. Neurosurg. Psychiatry 81, 192–197 (2010).

  85. 85.

    et al. Age-related changes in choroid plexus and blood–cerebrospinal fluid barrier function in the sheep. Exp. Gerontol. 44, 289–296 (2009).

  86. 86.

    & Cerebral microvascular pathology in aging and Alzheimer's disease. Prog. Neurobiol. 64, 575–611 (2001).

  87. 87.

    et al. Age, neuropathology, and dementia. N. Engl. J. Med. 360, 2302–2309 (2009).

  88. 88.

    Prevalence and impact of cerebrovascular lesions in Alzheimer and lewy body diseases. Neurodegener. Dis. 7, 112–115 (2010).

  89. 89.

    Brain microbleeds: more evidence, but still a clinical dilemma. Curr. Opin. Neurol. 24, 69–74 (2011).

  90. 90.

    & Cerebral amyloid angiopathy (CAA) in the elderly. Ann. Neurol. 10 Jun 2011 (doi:10.1002/ana.22516).

  91. 91.

    et al. Differential activation of mitochondrial apoptotic pathways by vasculotropic amyloid-β variants in cells composing the cerebral vessel walls. FASEB J. 24, 229–241 (2010).

  92. 92.

    et al. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nature Genet. 38, 24–26 (2006).

  93. 93.

    & IgG reactivity in the spinal cord and motor cortex in amyotrophic lateral sclerosis. Arch. Neurol. 47, 1210–1216 (1990).

  94. 94.

    et al. Evidence of compromised blood–spinal cord barrier in early and late symptomatic SOD1 mice modeling ALS. PLoS ONE 2, e1205 (2007).

  95. 95.

    et al. Amyotrophic lateral sclerosis: a neurovascular disease. Brain Res. 1398, 113–125 (2011).

  96. 96.

    , , , & TNF-α knockout and minocycline treatment attenuates blood–brain barrier leakage in MPTP-treated mice. Neurobiol. Dis. 26, 36–46 (2007).

  97. 97.

    , , , & Caffeine protects against MPTP-induced blood–brain barrier dysfunction in mouse striatum. J. Neurochem. 107, 1147–1157 (2008).

  98. 98.

    , & Mesenchymal stem cell transplantation attenuates blood brain barrier damage and neuroinflammation and protects dopaminergic neurons against MPTP toxicity in the substantia nigra in a model of Parkinson's disease. J. Neuroimmunol. 216, 39–50 (2009).

  99. 99.

    & Update in the epidemiology of Parkinson's disease. Curr. Opin. Neurol. 21, 454–460 (2008).

  100. 100.

    et al. Amyloid angiopathy in idiopathic Parkinson's disease. Immunohistochemical and ultrastructural study. Folia Neuropathol. 46, 255–270 (2008).

  101. 101.

    & Vascular parkinsonism: a clinical review. Eur. Neurol. 61, 11–15 (2009).

  102. 102.

    et al. Blood–brain barrier disruption in the striatum of rats treated with 3-nitropropionic acid. Neurotoxicology 30, 136–143 (2009).

  103. 103.

    , & GLUT-1 expression in the cerebra of patients with Alzheimer's disease. Neurobiol. Aging 18, 469–474 (1997).

  104. 104.

    et al. Reduced cerebral glucose metabolism in patients at risk for Alzheimer's disease. Psychiatry Res. 155, 147–154 (2007).

  105. 105.

    Cerebral glucose metabolism in preclinical and prodromal Alzheimer's disease. Expert Rev. Neurother. 10, 1667–1673 (2010).

  106. 106.

    et al. Hypometabolism exceeds atrophy in presymptomatic early-onset familial Alzheimer's disease. J. Nucl. Med. 47, 1778–1786 (2006).

  107. 107.

    et al. Partial volume effect-corrected FDG PET and grey matter volume loss in patients with mild Alzheimer's disease. Eur. J. Nucl. Med. Mol. Imaging 34, 1658–1669 (2007).

  108. 108.

    et al. Hippocampal hypometabolism predicts cognitive decline from normal aging. Neurobiol. Aging 29, 676–692 (2008).

  109. 109.

    , , , & β-Amyloid-mediated vasoactivity and vascular endothelial damage. Nature 380, 168–171 (1996). A study showing that amyloid-β constricts blood vessels.

  110. 110.

    et al. SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein. Nature Neurosci. 2, 157–161 (1999). A study showing that dysregulation in CBF occurs before amyloid-β deposition in a mouse model of Alzheimer's disease.

  111. 111.

    et al. Aβ1–40-related reduction in functional hyperemia in mouse neocortex during somatosensory activation. Proc. Natl Acad. Sci. USA 97, 9735–9740 (2000).

  112. 112.

    et al. Scavenger receptor CD36 is essential for the cerebrovascular oxidative stress and neurovascular dysfunction induced by amyloid-β. Proc. Natl Acad. Sci. USA 108, 5063–5068 (2011).

  113. 113.

    et al. Serum response factor and myocardin mediate arterial hypercontractility and cerebral blood flow dysregulation in Alzheimer's phenotype. Proc. Natl Acad. Sci. USA 104, 823–828 (2007). A study showing that elevated levels of myocardin and serum response factor lead to a hypercontractile phenotype of brain arteries in Alzheimer's disease.

  114. 114.

    et al. Blood–brain barrier P-glycoprotein function decreases in specific brain regions with aging: a possible role in progressive neurodegeneration. Neurobiol. Aging 30, 1818–1824 (2009).

  115. 115.

    et al. Decreased blood–brain barrier P-glycoprotein function in the progression of Parkinson's disease, PSP and MSA. J. Neural Transm. 115, 1001–1009 (2008).

  116. 116.

    , , & Gray matter perfusion correlates with disease severity in ALS. Neurology 74, 821–827 (2010).

  117. 117.

    et al. Reduced basal ganglia blood flow and volume in pre-symptomatic, gene-tested persons at-risk for Huntington's disease. Brain 122, 1667–1678 (1999).

  118. 118.

    & Vasomotor hyporeactivity in the anterior cerebral artery during motor activation in Huntington's disease patients. Brain Res. 872, 258–261 (2000).

  119. 119.

    & From angiogenesis to neuropathology. Nature 438, 954–959 (2005).

  120. 120.

    , , & Role and therapeutic potential of VEGF in the nervous system. Physiol. Rev. 89, 607–648 (2009).

  121. 121.

    , & Neurovascular signalling defects in neurodegeneration. Nature Rev. Neurosci. 9, 169–181 (2008).

  122. 122.

    et al. The cerebrospinal fluid provides a proliferative niche for neural progenitor cells. Neuron 69, 893–905 (2011).

  123. 123.

    et al. Impaired angiogenesis in a transgenic mouse model of cerebral amyloidosis. Neurosci. Lett. 366, 80–85 (2004).

  124. 124.

    , , , & Cadasil. Lancet Neurol. 8, 643–653 (2009).

  125. 125.

    et al. Glut1 deficiency: inheritance pattern determined by haploinsufficiency. Ann. Neurol. 68, 955–958 (2010).

  126. 126.

    et al. A mouse model for Glut-1 haploinsufficiency. Hum. Mol. Genet. 15, 1169–1179 (2006).

  127. 127.

    et al. Peripherally applied Aβ-containing inoculates induce cerebral β-amyloidosis. Science 330, 980–982 (2010). A study showing that peripheral amyloid-β contributes to the development of cerebral β-amyloidosis in a mouse model of Alzheimer's disease.

  128. 128.

    , , , & Peripheral reduction of β-amyloid is sufficient to reduce brain β-amyloid: implications for Alzheimer's disease. J. Neurosci. Res. 89, 808–814 (2011).

  129. 129.

    , , , & From the liver to the blood–brain barrier: an interconnected system regulating brain amyloid-β levels. J. Neurosci. Res. 89, 967–968 (2011).

  130. 130.

    , , & Blood–brain barrier permeability precedes senile plaque formation in an Alzheimer disease model. Microcirculation 10, 463–470 (2003).

  131. 131.

    et al. Circulating amyloid-β peptide crosses the blood–brain barrier in aged monkeys and contributes to Alzheimer's disease lesions. Vascul. Pharmacol. 38, 303–313 (2002).

  132. 132.

    et al. Cerebrovascular accumulation and increased blood–brain barrier permeability to circulating Alzheimer's amyloid β peptide in aged squirrel monkey with cerebral amyloid angiopathy. J. Neurochem. 70, 210–215 (1998).

  133. 133.

    , , , & Permeability and residual plasma volume of human, Dutch variant, and rat amyloid β-protein 1–40 at the blood–brain barrier. Neurobiol. Dis. 4, 27–34 (1997).

  134. 134.

    et al. Intra-arterial infusion of 125IAβ 1–40 labels amyloid deposits in the aged primate brain in vivo. Neuroreport 7, 2607–2611 (1996).

  135. 135.

    et al. Blood–brain barrier transport of circulating Alzheimer's amyloid β. Biochem. Biophys. Res. Commun. 197, 1034–1040 (1993).

  136. 136.

    , , , & Blood–brain barrier uptake of the 40 and 42 amino acid sequences of circulating Alzheimer's amyloid β in guinea pigs. Neurosci. Lett. 206, 157–160 (1996).

  137. 137.

    et al. Clearance of amyloid-β by circulating lipoprotein receptors. Nature Med. 13, 1029–1031 (2007). A study showing that soluble LRP1 binds amyloid-β in the cirulation, preventing re-entry of this peptide into the brain.

  138. 138.

    , , , & Brain to plasma amyloid-β efflux: a measure of brain amyloid burden in a mouse model of Alzheimer's disease. Science 295, 2264–2267 (2002). A study showing that a circulating anti-amyloid-β antibody promotes efflux of this peptide from brain to blood.

  139. 139.

    , , , & Immunization with a nontoxic/nonfibrillar amyloid-β homologous peptide reduces Alzheimer's disease-associated pathology in transgenic mice. Am. J. Pathol. 159, 439–447 (2001).

  140. 140.

    et al. Plaque-associated disruption of CSF and plasma amyloid-β (Aβ) equilibrium in a mouse model of Alzheimer's disease. J. Neurochem. 81, 229–236 (2002).

  141. 141.

    et al. Novel therapeutic approach for the treatment of Alzheimer's disease by peripheral administration of agents with an affinity to β-amyloid. J. Neurosci. 23, 29–33 (2003).

  142. 142.

    et al. Expression of neprilysin in skeletal muscle reduces amyloid burden in a transgenic mouse model of Alzheimer disease. Mol. Ther. 17, 1381–1386 (2009).

  143. 143.

    et al. Circulating neprilysin clears brain amyloid. Mol. Cell. Neurosci. 45, 101–107 (2010).

  144. 144.

    et al. RAGE mediates amyloid-β peptide transport across the blood–brain barrier and accumulation in brain. Nature Med. 9, 907–913 (2003). A study showing that RAGE mediates the influx of amyloid-β into the brain across the BBB.

  145. 145.

    et al. Human blood–brain barrier receptors for Alzheimer's amyloid-β 1–40. Asymmetrical binding, endocytosis, and transcytosis at the apical side of brain microvascular endothelial cell monolayer. J. Clin. Invest. 102, 734–743 (1998).

  146. 146.

    et al. β-amyloid-induced migration of monocytes across human brain endothelial cells involves RAGE and PECAM-1. Am. J. Physiol. Cell Physiol. 279, C1772–C1781 (2000).

  147. 147.

    et al. RAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease. Nature 382, 685–691 (1996).

  148. 148.

    , & The RAGE axis: a fundamental mechanism signaling danger to the vulnerable vasculature. Circ. Res. 106, 842–853 (2010).

  149. 149.

    et al. Decreased clearance of CNS β-amyloid in Alzheimer's disease. Science 330, 1774 (2010). An important study demonstrating faulty amyloid-β clearance from the brain in patients with Alzheimer's disease.

  150. 150.

    , , , & Low-density lipoprotein receptor-related protein-1: a serial clearance homeostatic mechanism controlling Alzheimer's amyloid β-peptide elimination from the brain. J. Neurochem. 115, 1077–1089 (2010).

  151. 151.

    et al. LRP/amyloid β-peptide interaction mediates differential brain efflux of Aβ isoforms. Neuron 43, 333–344 (2004).

  152. 152.

    et al. Clearance of Alzheimer's amyloid-β1–40 peptide from brain by LDL receptor-related protein-1 at the blood–brain barrier. J. Clin. Invest. 106, 1489–1499 (2000). A pioneering study showing that LRP1 medaites amyloid-β clearance from the brain to the blood across the BBB.

  153. 153.

    et al. Transport pathways for clearance of human Alzheimer's amyloid β-peptide and apolipoproteins E and J in the mouse central nervous system. J. Cereb. Blood Flow Metab. 27, 909–918 (2007).

  154. 154.

    et al. Testing the neurovascular hypothesis of Alzheimer's disease: LRP-1 antisense reduces blood–brain barrier clearance, increases brain levels of amyloid-β protein, and impairs cognition. J. Alzheimers Dis. 17, 553–570 (2009).

  155. 155.

    et al. Reduction of brain β-amyloid (Aβ) by fluvastatin, a hydroxymethylglutaryl-CoA reductase inhibitor, through increase in degradation of amyloid precursor protein C-terminal fragments (APP-CTFs) and Aβ clearance. J. Biol. Chem. 285, 22091–22102 (2010).

  156. 156.

    et al. Lipopolysaccharide alters the blood–brain barrier transport of amyloid β protein: a mechanism for inflammation in the progression of Alzheimer's disease. Brain Behav. Immun. 23, 507–517 (2009).

  157. 157.

    et al. The low density lipoprotein receptor-related protein 1 mediates uptake of amyloid β peptides in an in vitro model of the blood-brain barrier cells. J. Biol. Chem. 283, 34554–34562 (2008).

  158. 158.

    , & LRP promotes endocytosis and degradation, but not transcytosis, of the amyloid-β peptide in a blood–brain barrier in vitro model. Neurobiol. Dis. 30, 94–102 (2008).

  159. 159.

    et al. Substitution at codon 22 reduces clearance of Alzheimer's amyloid-β peptide from the cerebrospinal fluid and prevents its transport from the central nervous system into blood. Neurobiol. Aging 23, 405–412 (2002).

  160. 160.

    et al. Early-onset and robust cerebral microvascular accumulation of amyloid β-protein in transgenic mice expressing low levels of a vasculotropic Dutch/Iowa mutant form of amyloid β-protein precursor. J. Biol. Chem. 279, 20296–20306 (2004).

  161. 161.

    et al. apoE isoform-specific disruption of amyloid β peptide clearance from mouse brain. J. Clin. Invest. 118, 4002–4013 (2008).

  162. 162.

    et al. ApoE and clusterin cooperatively suppress Aβ levels and deposition: evidence that ApoE regulates extracellular Aβ metabolism in vivo. Neuron 41, 193–202 (2004).

  163. 163.

    et al. Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer's disease. Proc. Natl Acad. Sci. USA 99, 10843–10848 (2002).

  164. 164.

    et al. Brain clearance of Alzheimer's amyloid-β40 in the squirrel monkey: a SPECT study in a primate model of cerebral amyloid angiopathy. J. Drug Target. 10, 359–368 (2002).

  165. 165.

    et al. RAGE, LRP-1, and amyloid-β protein in Alzheimer's disease. Acta Neuropathol. 112, 405–415 (2006).

  166. 166.

    et al. P-glycoprotein deficiency at the blood–brain barrier increases amyloid-β deposition in an Alzheimer disease mouse model. J. Clin. Invest. 115, 3285–3290 (2005).

  167. 167.

    et al. Oxidative modification to LDL receptor-related protein 1 in hippocampus from subjects with Alzheimer disease: implications for Aβ accumulation in AD brain. Free Radic. Biol. Med. 49, 1798–1803 (2010).

  168. 168.

    et al. Lead-induced accumulation of β-amyloid in the choroid plexus: role of low density lipoprotein receptor protein-1 and protein kinase C. Neurotoxicology 31, 524–532 (2010).

  169. 169.

    et al. Impaired lipoprotein receptor-mediated peripheral binding of plasma amyloid-β is an early biomarker for mild cognitive impairment preceding Alzheimer's disease. J. Alzheimers Dis. 24, 25–34 (2011).

  170. 170.

    et al. Major involvement of low-density lipoprotein receptor-related protein 1 in the clearance of plasma free amyloid β-peptide by the liver. Pharm. Res. 23, 1407–1416 (2006).

  171. 171.

    et al. Metabolic regulation of brain Aβ by neprilysin. Science 292, 1550–1552 (2001).

  172. 172.

    & Insulin, insulin-degrading enzyme and amyloid-β peptide in Alzheimer's disease: review and hypothesis. Neurobiol. Aging 27, 190–198 (2006).

  173. 173.

    , & The tissue plasminogen activator-plasminogen proteolytic cascade accelerates amyloid-β (Aβ) degradation and inhibits Aβ-induced neurodegeneration. J. Neurosci. 23, 8867–8871 (2003).

  174. 174.

    et al. Matrix metalloproteinases expressed by astrocytes mediate extracellular amyloid-β peptide catabolism. J. Neurosci. 26, 10939–10948 (2006).

  175. 175.

    et al. Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-β peptides. Nature Med. 10, 719–726 (2004).

  176. 176.

    et al. Non-Fc-mediated mechanisms are involved in clearance of amyloid-β in vivo by immunotherapy. J. Neurosci. 22, 7873–7878 (2002).

  177. 177.

    , & Microglial dysfunction and defective β-amyloid clearance pathways in aging Alzheimer's disease mice. J. Neurosci. 28, 8354–8360 (2008).

  178. 178.

    , , , & Perivascular drainage of amyloid-β peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer's disease. Brain Pathol. 18, 253–266 (2008).

  179. 179.

    et al. Amyloid-β dynamics correlate with neurological status in the injured human brain. Science 321, 1221–1224 (2008).

  180. 180.

    & Alzheimer's disease. N.Engl. J. Med. 362, 329–344 (2010).

  181. 181.

    The amyloid hypothesis for Alzheimer's disease: a critical reappraisal. J. Neurochem. 110, 1129–1134 (2009).

  182. 182.

    & Neurodegeneration: an expansion in ALS genetics. Nature 466, 1052–1053 (2010).

  183. 183.

    , & Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J. Cell Biol. 187, 761–772 (2009).

  184. 184.

    et al. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466, 1069–1075 (2010).

  185. 185.

    et al. Common molecular signature in SOD1 for both sporadic and familial amyotrophic lateral sclerosis. Proc. Natl Acad. Sci. USA 104, 12524–12529 (2007).

  186. 186.

    et al. Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312, 1389–1392 (2006). A study demonstrating that the toxicity conferred by an ALS-linked SOD1 mutant to microglia determines the lifespan of mice with an ALS-like disease.

  187. 187.

    et al. Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nature Neurosci. 11, 251–253 (2008).

  188. 188.

    et al. Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc. Natl Acad. Sci. USA 103, 16021–16026 (2006).

  189. 189.

    , , , & Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nature Neurosci. 10, 608–614 (2007).

  190. 190.

    et al. Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nature Neurosci. 10, 615–622 (2007).

  191. 191.

    et al. VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nature Genet. 34, 383–394 (2003).

  192. 192.

    et al. ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis. Nature Genet. 38, 411–413 (2006).

  193. 193.

    et al. Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nature Genet. 28, 131–138 (2001).

  194. 194.

    , , , & Alzheimer's disease: clinical trials and drug development. Lancet Neurol. 9, 702–716 (2010).

  195. 195.

    & Cytoprotective protein C pathways and implications for stroke and neurological disorders. Trends Neurosci. 34, 198–209 (2011).

  196. 196.

    et al. Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS. Nature Neurosci. 8, 85–92 (2005).

  197. 197.

    et al. VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature 429, 413–417 (2004).

  198. 198.

    US National Institutes of Health. A safety and tolerability study of intracerebroventricular administration of sNN0029 to patients with amyotrophic lateral sclerosis. ClinicalTrials.gov , (2011).

  199. 199.

    et al. Control of motoneuron survival by angiogenin. J. Neurosci. 28, 14056–14061 (2008).

  200. 200.

    , , , & Disturbed cross talk between insulin-like growth factor I and AMP-activated protein kinase as a possible cause of vascular dysfunction in the amyloid precursor protein/presenilin 2 mouse model of Alzheimer's disease. J. Neurosci. 27, 824–831 (2007).

  201. 201.

    et al. The effect of encapsulated VEGF-secreting cells on brain amyloid load and behavioral impairment in a mouse model of Alzheimer's disease. Biomaterials 31, 5608–5618 (2010).

  202. 202.

    The benefits and limitations of animal models for translational research in neurodegenerative diseases. Nature Med. 16, 1210–1214 (2010).

  203. 203.

    Degeneration and repair in central nervous system disease. Nature Med. 16, 1205–1209 (2010).

  204. 204.

    The future of genetic research on neurodegeneration. Nature Med. 16, 1215–1217 (2010).

  205. 205.

    Vascular risk factor detection and control may prevent Alzheimer's disease. Ageing Res. Rev. 9, 218–225 (2010).

  206. 206.

    et al. Relation of diabetes to mild cognitive impairment. Arch. Neurol. 64, 570–575 (2007).

  207. 207.

    & Hypertension and cerebrovascular dysfunction. Cell Metab. 7, 476–484 (2008).

  208. 208.

    et al. Central obesity and increased risk of dementia more than three decades later. Neurology 71, 1057–1064 (2008).

  209. 209.

    Alzheimer's dementia begins as a disease of small blood vessels, damaged by oxidative-induced inflammation and dysregulated amyloid metabolism: implications for early detection and therapy. FASEB J. 25, 5–13 (2011).

  210. 210.

    et al. Silent brain infarcts and the risk of dementia and cognitive decline. N. Engl. J. Med. 348, 1215–1222 (2003).

  211. 211.

    et al. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA 277, 813–817 (1997).

  212. 212.

    et al. Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets. Nature 451, 1076–1081 (2008).

Download references

Acknowledgements

The author wishes to thank the US National Institutes of Health (grants R37 AG023084, R37 NS34467 and HL63290), the ALS Association (grant 1859) and the Zilkha family for research support. The author also wishes to thank A. Sagare for preparing the illustrations and for valuable help with the reference list.

Author information

Affiliations

  1. Department of Physiology and Biophysics, and Center for Neurodegeneration and Regeneration at the Zilkha Neurogenetic Institute, University of Southern California, Keck School of Medicine, 1501 San Pablo Street, Los Angeles, California 90089, USA.  bzlokovi@usc.edu

    • Berislav V. Zlokovic

Authors

  1. Search for Berislav V. Zlokovic in:

Competing interests

Berislav V. Zlokovic is the scientific founder of Socratech LLC, a start-up biotechnology company with a mission to develop new therapeutic approaches for stroke and Alzheimer's disease.

Glossary

Blood–brain barrier

(BBB). A continuous endothelial cell membrane within the neurovascular unit that regulates the entry of cells and molecules into the brain, and maintains the removal of potentially neurotoxic molecules from the brain to blood.

Cerebral β-amyloidosis

This is a key pathological feature of Alzheimer's disease and is caused by accumulation and aggregation of amyloid-β in brain parenchyma.

Cerebral amyloid angiopathy

A vessel disease that is caused by the deposition of amyloid in the vessel wall of small cerebral arteries and capillaries, and that results in cerebral blood flow dysregulation, blood–brain barrier disruption and microhaemorrhages.

Amyloid-β

A small, 4-kDa peptide that accumulates in the brains of individuals with Alzheimer's disease. It forms neurotoxic oligomers and amyloid aggregates that are deposited in the brain parenchyma and around small cerebral blood vessels.

Neurovascular unit

A complex multicellular functional unit of the CNS comprising vascular cells, glial cells and neurons that, together, ultimately determine CNS activities and responses in health and disease.

Pericytes

Mural vascular cells that share a common basement membrane with brain capillary endothelial cells at one end, and that are in direct contact with astrocytes at the other.

Protein C

An endogenous protease that in its active form — activated protein C (APC) — is a prototype of a new, neurovascular medicine that exerts multiple beneficial effects by acting on different types of non-neuronal cells within the neurovascular unit.

Low-density lipoprotein receptor-related protein 1

(LRP1). A cargo endocytic receptor mediating cellular internalization of multiple ligands as well as cell signalling in various cell types of the neurovascular unit.

Neurovascular coupling

This involves a functional change in cerebral blood flow that occurs in accordance, both temporally and spatially, with a change in neuronal activity.

Oligaemia

This is a moderate deficit in the resting cerebral blood flow that, if it persists, often leads to the chronic hypoperfusion and hypoxia in the CNS that is frequently found in the major neurodegenerative disorders before neurodegeneration.

Pinocytosis

This is the nonspecific transport of fluid-filled vesicles across the endothelial cells in capillaries of peripheral organs.

Neurovascular uncoupling

A term defining a diminished cerebral blood flow response to brain activation.

Trojan horses

In relation to the blood–brain barrier, this term is frequently used to describe the facilitated delivery into the brain of an otherwise non-transportable neuroactive therapeutic protein through the formation of a complex with another protein.