Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders (original) (raw)

• Zlokovic, B. V. The blood–brain barrier in health and chronic neurodegenerative disorders. Neuron 57, 178–201 (2008).
  Article CAS PubMed Google Scholar
• Moskowitz, M. A., Lo, E. H. & Iadecola, C. 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.
  Article CAS PubMed PubMed Central Google Scholar
• Zlokovic, B. V. Neurovascular mechanisms of Alzheimer's neurodegeneration. Trends Neurosci. 28, 202–208 (2005).
  Article CAS PubMed Google Scholar
• Brown, W. R. & Thore, C. R. Review: cerebral microvascular pathology in ageing and neurodegeneration. Neuropathol. Appl. Neurobiol. 37, 56–74 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Wu, Z. 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.
  Article CAS PubMed Google Scholar
• Paul, J., Strickland, S. & Melchor, J. P. 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.
  Article CAS PubMed PubMed Central Google Scholar
• Zipser, B. D. et al. Microvascular injury and blood–brain barrier leakage in Alzheimer's disease. Neurobiol. Aging 28, 977–986 (2007).
  Article CAS PubMed Google Scholar
• Zhong, Z. 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.
  Article CAS PubMed Google Scholar
• Kalaria, R. N. Vascular basis for brain degeneration: faltering controls and risk factors for dementia. Nutr. Rev. 68, S74–S87 (2010).
  Article PubMed Google Scholar
• Knopman, D. S. & Roberts, R. Vascular risk factors: imaging and neuropathologic correlates. J. Alzheimers Dis. 20, 699–709 (2010).
  Article PubMed PubMed Central Google Scholar
• Miyazaki, K. et al. Disruption of neurovascular unit prior to motor neuron degeneration in amyotrophic lateral sclerosis. J. Neurosci. Res. 89, 718–728 (2011).
  Article CAS PubMed Google Scholar
• Neuwelt, E. A. et al. Engaging neuroscience to advance translational research in brain barrier biology. Nature Rev. Neurosci. 12, 169–182 (2011).
  Article CAS Google Scholar
• Guo, S. & Lo, E. H. Dysfunctional cell–cell signaling in the neurovascular unit as a paradigm for central nervous system disease. Stroke 40, S4–S7 (2009).
  Article PubMed Google Scholar
• Redzic, Z. Molecular biology of the blood–brain and the blood–cerebrospinal fluid barriers: similarities and differences. Fluids Barriers CNS 8, 3 (2011).
  Article PubMed PubMed Central Google Scholar
• O'Kane, R. L., Martinez-Lopez, I., DeJoseph, M. R., Vina, J. R. & Hawkins, R. A. 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).
  Article CAS PubMed Google Scholar
• Hardingham, G. E. Coupling of the NMDA receptor to neuroprotective and neurodestructive events. Biochem. Soc. Trans. 37, 1147–1160 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Elali, A. & Hermann, D. M. ATP-binding cassette transporters and their roles in protecting the brain. Neuroscientist 17, 423–436 (2011).
  Article CAS PubMed Google Scholar
• Visser, W. E., Friesema, E. C. & Visser, T. J. Minireview: thyroid hormone transporters: the knowns and the unknowns. Mol. Endocrinol. 25, 1–14 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Zlokovic, B. V., Begley, D. J. & Chain-Eliash, D. G. 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).
  Article CAS PubMed Google Scholar
• Zlokovic, B. V., Lipovac, M. N., Begley, D. J., Davson, H. & Rakic, L. Transport of leucine-enkephalin across the blood–brain barrier in the perfused guinea pig brain. J. Neurochem. 49, 310–315 (1987).
  Article CAS PubMed Google Scholar
• Zlokovic, B. V., Mackic, J. B., Djuricic, B. & Davson, H. 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).
  Article CAS PubMed Google Scholar
• Zlokovic, B. V. et al. Kinetics of arginine-vasopressin uptake at the blood–brain barrier. Biochim. Biophys. Acta 1025, 191–198 (1990).
  Article CAS PubMed Google Scholar
• Zlokovic, B. V., Segal, M. B., Begley, D. J., Davson, H. & Rakic, L. Permeability of the blood–cerebrospinal fluid and blood–brain barriers to thyrotropin-releasing hormone. Brain Res. 358, 191–199 (1985).
  Article CAS PubMed Google Scholar
• Dogrukol-Ak, D. 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).
  Article CAS PubMed Google Scholar
• Pardridge, W. M. Blood–brain barrier delivery. Drug Discov. Today 12, 54–61 (2007).
  Article CAS PubMed Google Scholar
• Nishijima, T. 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).
  Article CAS PubMed Google Scholar
• Banks, W. A. Blood–brain barrier as a regulatory interface. Forum Nutr. 63, 102–110 (2010).
  Article CAS PubMed Google Scholar
• Deane, R. 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).
  Article CAS PubMed Google Scholar
• Iadecola, C. Astrocytes take center stage in salt sensing. Neuron 54, 3–5 (2007).
  Article CAS PubMed Google Scholar
• Shimizu, H. et al. Glial Nax channels control lactate signaling to neurons for brain [Na+] sensing. Neuron 54, 59–72 (2007).
  Article CAS PubMed Google Scholar
• Henkel, J. S., Beers, D. R., Wen, S., Bowser, R. & Appel, S. H. Decreased mRNA expression of tight junction proteins in lumbar spinal cords of patients with ALS. Neurology 72, 1614–1616 (2009).
  Article CAS PubMed Google Scholar
• Alvarez, J. I., Cayrol, R. & Prat, A. Disruption of central nervous system barriers in multiple sclerosis. Biochim. Biophys. Acta 1812, 252–264 (2011).
  Article CAS PubMed Google Scholar
• Bell, R. D. 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.
  Article CAS PubMed PubMed Central Google Scholar
• Rosenberg, G. A. Matrix metalloproteinases and their multiple roles in neurodegenerative diseases. Lancet Neurol. 8, 205–216 (2009).
  Article CAS PubMed Google Scholar
• Cheng, T. et al. Activated protein C inhibits tissue plasminogen activator-induced brain hemorrhage. Nature Med. 12, 1278–1285 (2006).
  Article CAS PubMed Google Scholar
• Daneman, R., Zhou, L., Kebede, A. A. & Barres, B. A. 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.
  Article CAS PubMed PubMed Central Google Scholar
• Li, F. 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.
  Article CAS PubMed Google Scholar
• Armulik, A. 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.
  Article CAS PubMed Google Scholar
• Broadwell, R. D. & Salcman, M. Expanding the definition of the blood–brain barrier to protein. Proc. Natl Acad. Sci. USA 78, 7820–7824 (1981).
  Article CAS PubMed PubMed Central Google Scholar
• Mhatre, M. et al. Thrombin, a mediator of neurotoxicity and memory impairment. Neurobiol. Aging 25, 783–793 (2004).
  Article CAS PubMed Google Scholar
• Chen, B., Cheng, Q., Yang, K. & Lyden, P. D. Thrombin mediates severe neurovascular injury during ischemia. Stroke 41, 2348–2352 (2010).
  Article CAS PubMed Google Scholar
• Chen, Z. L. & Strickland, S. Neuronal death in the hippocampus is promoted by plasmin-catalyzed degradation of laminin. Cell 91, 917–925 (1997).
  Article CAS PubMed Google Scholar
• Zhong, Z. 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.
  CAS PubMed PubMed Central Google Scholar
• Simard, J. M., Kent, T. A., Chen, M., Tarasov, K. V. & Gerzanich, V. Brain oedema in focal ischaemia: molecular pathophysiology and theoretical implications. Lancet Neurol. 6, 258–268 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Hoshi, A., Yamamoto, T., Shimizu, K., Sugiura, Y. & Ugawa, Y. Chemical preconditioning-induced reactive astrocytosis contributes to the reduction of post-ischemic edema through aquaporin-4 downregulation. Exp. Neurol. 227, 89–95 (2011).
  Article CAS PubMed Google Scholar
• Iadecola, C. Neurovascular regulation in the normal brain and in Alzheimer's disease. Nature Rev. Neurosci. 5, 347–360 (2004).
  Article CAS Google Scholar
• Peppiatt, C. M., Howarth, C., Mobbs, P. & Attwell, D. 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.
  Article CAS PubMed PubMed Central Google Scholar
• Yemisci, M. 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).
  Article CAS PubMed Google Scholar
• Kuchibhotla, K. V., Lattarulo, C. R., Hyman, B. T. & Bacskai, B. J. Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science 323, 1211–1215 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Takano, T., Han, X., Deane, R., Zlokovic, B. & Nedergaard, M. 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).
  Article CAS PubMed Google Scholar
• Smith, C. D. et al. Altered brain activation in cognitively intact individuals at high risk for Alzheimer's disease. Neurology 53, 1391–1396 (1999).
  Article CAS PubMed Google Scholar
• Bookheimer, S. Y. et al. Patterns of brain activation in people at risk for Alzheimer's disease. N. Engl. J. Med. 343, 450–456 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Ruitenberg, A. et al. Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam Study. Ann. Neurol. 57, 789–794 (2005).
  Article PubMed Google Scholar
• Sheline, Y. I. 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).
  Article CAS PubMed PubMed Central Google Scholar
• Wang, X. et al. Cerebrovascular hypoperfusion induces spatial memory impairment, synaptic changes, and amyloid-β oligomerization in rats. J. Alzheimers Dis. 21, 813–822 (2010).
  Article CAS PubMed Google Scholar
• Walsh, D. M. 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.
  Article CAS PubMed Google Scholar
• Koike, M. A., Green, K. N., Blurton-Jones, M. & Laferla, F. M. Oligemic hypoperfusion differentially affects tau and amyloid-β. Am. J. Pathol. 177, 300–310 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Gordon-Krajcer, W., Kozniewska, E., Lazarewicz, J. W. & Ksiezak-Reding, H. 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).
  Article CAS PubMed Google Scholar
• Ongali, B. 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).
  Article CAS PubMed PubMed Central Google Scholar
• Sun, X. et al. Hypoxia facilitates Alzheimer's disease pathogenesis by up-regulating BACE1 gene expression. Proc. Natl Acad. Sci. USA 103, 18727–18732 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, X. et al. Hypoxia-inducible factor 1α (HIF-1α)-mediated hypoxia increases BACE1 expression and β-amyloid generation. J. Biol. Chem. 282, 10873–10880 (2007).
  Article CAS PubMed Google Scholar
• Guglielmotto, M. 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).
  Article CAS PubMed Google Scholar
• Li, L. et al. Hypoxia increases Aβ generation by altering β- and γ-cleavage of APP. Neurobiol. Aging 30, 1091–1098 (2009).
  Article CAS PubMed Google Scholar
• Fang, H., Zhang, L. F., Meng, F. T., Du, X. & Zhou, J. N. Acute hypoxia promote the phosphorylation of tau via ERK pathway. Neurosci. Lett. 474, 173–177 (2010).
  Article CAS PubMed Google Scholar
• Wang, Z. et al. Hypoxia-induced down-regulation of neprilysin by histone modification in mouse primary cortical and hippocampal neurons. PLoS ONE 6, e19229 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Bell, R. D. 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.
  Article CAS PubMed Google Scholar
• Munch, C. et al. Chemical hypoxia facilitates alternative splicing of EAAT2 in presymptomatic APP23 transgenic mice. Neurochem. Res. 33, 1005–1010 (2008).
  Article CAS PubMed Google Scholar
• Boycott, H. E., Dallas, M., Boyle, J. P., Pearson, H. A. & Peers, C. Hypoxia suppresses astrocyte glutamate transport independently of amyloid formation. Biochem. Biophys. Res. Commun. 364, 100–104 (2007).
  Article CAS PubMed Google Scholar
• Carvalho, C. et al. Role of mitochondrial-mediated signaling pathways in Alzheimer disease and hypoxia. J. Bioenerg. Biomembr. 41, 433–440 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Fernandez-Checa, J. C. et al. Oxidative stress and altered mitochondrial function in neurodegenerative diseases: lessons from mouse models. CNS Neurol. Disord. Drug Targets 9, 439–454 (2010).
  Article CAS PubMed Google Scholar
• Correia, S. C. et al. Mitochondria: the missing link between preconditioning and neuroprotection. J. Alzheimers Dis. 20, S475–S485 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Glass, C. K., Saijo, K., Winner, B., Marchetto, M. C. & Gage, F. H. Mechanisms underlying inflammation in neurodegeneration. Cell 140, 918–934 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Grammas, P. Neurovascular dysfunction, inflammation and endothelial activation: implications for the pathogenesis of Alzheimer's disease. J. Neuroinflammation 8, 26 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Grammas, P., Moore, P. & Weigel, P. H. Microvessels from Alzheimer's disease brains kill neurons in vitro. Am. J. Pathol. 154, 337–342 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Moser, K. V., Stockl, P. & Humpel, C. 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).
  Article CAS PubMed Google Scholar
• Yin, X., Wright, J., Wall, T. & Grammas, P. Brain endothelial cells synthesize neurotoxic thrombin in Alzheimer's disease. Am. J. Pathol. 176, 1600–1606 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Martin, A. J., Friston, K. J., Colebatch, J. G. & Frackowiak, R. S. Decreases in regional cerebral blood flow with normal aging. J. Cereb. Blood Flow Metab. 11, 684–689 (1991).
  Article CAS PubMed Google Scholar
• Li, B. & Freeman, R. D. Neurometabolic coupling in the lateral geniculate nucleus changes with extended age. J. Neurophysiol. 104, 414–425 (2010).
  Article PubMed PubMed Central Google Scholar
• Bertram, L., McQueen, M. B., Mullin, K., Blacker, D. & Tanzi, R. E. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nature Genet. 39, 17–23 (2007).
  Article CAS PubMed Google Scholar
• Kim, J., Basak, J. M. & Holtzman, D. M. The role of apolipoprotein E in Alzheimer's disease. Neuron 63, 287–303 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Verghese, P. B., Castellano, J. M. & Holtzman, D. M. Apolipoprotein E in Alzheimer's disease and other neurological disorders. Lancet Neurol. 10, 241–252 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Thambisetty, M., Beason-Held, L., An, Y., Kraut, M. A. & Resnick, S. M. APOE ɛ4 genotype and longitudinal changes in cerebral blood flow in normal aging. Arch. Neurol. 67, 93–98 (2010).
  Article PubMed PubMed Central Google Scholar
• Farrall, A. J. & Wardlaw, J. M. Blood–brain barrier: ageing and microvascular disease — systematic review and meta-analysis. Neurobiol. Aging 30, 337–352 (2009).
  Article CAS PubMed Google Scholar
• Topakian, R., Barrick, T. R., Howe, F. A. & Markus, H. S. 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).
  Article CAS PubMed Google Scholar
• Chen, R. L. et al. Age-related changes in choroid plexus and blood–cerebrospinal fluid barrier function in the sheep. Exp. Gerontol. 44, 289–296 (2009).
  Article CAS PubMed Google Scholar
• Farkas, E. & Luiten, P. G. Cerebral microvascular pathology in aging and Alzheimer's disease. Prog. Neurobiol. 64, 575–611 (2001).
  Article CAS PubMed Google Scholar
• Savva, G. M. et al. Age, neuropathology, and dementia. N. Engl. J. Med. 360, 2302–2309 (2009).
  Article CAS PubMed Google Scholar
• Jellinger, K. A. Prevalence and impact of cerebrovascular lesions in Alzheimer and lewy body diseases. Neurodegener. Dis. 7, 112–115 (2010).
  Article CAS PubMed Google Scholar
• Cordonnier, C. Brain microbleeds: more evidence, but still a clinical dilemma. Curr. Opin. Neurol. 24, 69–74 (2011).
  Article PubMed Google Scholar
• Viswanathan, A. & Greenberg, S. M. Cerebral amyloid angiopathy (CAA) in the elderly. Ann. Neurol. 10 Jun 2011 (doi:10.1002/ana.22516).
  Article CAS PubMed PubMed Central Google Scholar
• Fossati, S. 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).
  Article CAS PubMed PubMed Central Google Scholar
• Rovelet-Lecrux, A. et al. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nature Genet. 38, 24–26 (2006).
  Article CAS PubMed Google Scholar
• Engelhardt, J. I. & Appel, S. H. IgG reactivity in the spinal cord and motor cortex in amyotrophic lateral sclerosis. Arch. Neurol. 47, 1210–1216 (1990).
  Article CAS PubMed Google Scholar
• Garbuzova-Davis, S. et al. Evidence of compromised blood–spinal cord barrier in early and late symptomatic SOD1 mice modeling ALS. PLoS ONE 2, e1205 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Garbuzova-Davis, S. et al. Amyotrophic lateral sclerosis: a neurovascular disease. Brain Res. 1398, 113–125 (2011).
  Article CAS PubMed Google Scholar
• Zhao, C., Ling, Z., Newman, M. B., Bhatia, A. & Carvey, P. M. TNF-α knockout and minocycline treatment attenuates blood–brain barrier leakage in MPTP-treated mice. Neurobiol. Dis. 26, 36–46 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Chen, X., Lan, X., Roche, I., Liu, R. & Geiger, J. D. Caffeine protects against MPTP-induced blood–brain barrier dysfunction in mouse striatum. J. Neurochem. 107, 1147–1157 (2008).
  CAS PubMed PubMed Central Google Scholar
• Chao, Y. X., He, B. P. & Tay, S. S. 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).
  Article CAS PubMed Google Scholar
• Elbaz, A. & Moisan, F. Update in the epidemiology of Parkinson's disease. Curr. Opin. Neurol. 21, 454–460 (2008).
  Article PubMed Google Scholar
• Bertrand, E. et al. Amyloid angiopathy in idiopathic Parkinson's disease. Immunohistochemical and ultrastructural study. Folia Neuropathol. 46, 255–270 (2008).
  PubMed Google Scholar
• Benamer, H. T. & Grosset, D. G. Vascular parkinsonism: a clinical review. Eur. Neurol. 61, 11–15 (2009).
  Article PubMed Google Scholar
• Duran-Vilaregut, J. et al. Blood–brain barrier disruption in the striatum of rats treated with 3-nitropropionic acid. Neurotoxicology 30, 136–143 (2009).
  Article CAS PubMed Google Scholar
• Mooradian, A. D., Chung, H. C. & Shah, G. N. GLUT-1 expression in the cerebra of patients with Alzheimer's disease. Neurobiol. Aging 18, 469–474 (1997).
  Article CAS PubMed Google Scholar
• Hunt, A. et al. Reduced cerebral glucose metabolism in patients at risk for Alzheimer's disease. Psychiatry Res. 155, 147–154 (2007).
  Article CAS PubMed Google Scholar
• Herholz, K. Cerebral glucose metabolism in preclinical and prodromal Alzheimer's disease. Expert Rev. Neurother. 10, 1667–1673 (2010).
  Article CAS PubMed Google Scholar
• Mosconi, L. et al. Hypometabolism exceeds atrophy in presymptomatic early-onset familial Alzheimer's disease. J. Nucl. Med. 47, 1778–1786 (2006).
  CAS PubMed Google Scholar
• Samuraki, M. 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).
  Article PubMed Google Scholar
• Mosconi, L. et al. Hippocampal hypometabolism predicts cognitive decline from normal aging. Neurobiol. Aging 29, 676–692 (2008).
  Article CAS PubMed Google Scholar
• Thomas, T., Thomas, G., McLendon, C., Sutton, T. & Mullan, M. β-Amyloid-mediated vasoactivity and vascular endothelial damage. Nature 380, 168–171 (1996). A study showing that amyloid-β constricts blood vessels.
  Article CAS PubMed Google Scholar
• Iadecola, C. 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.
  Article CAS PubMed Google Scholar
• Niwa, K. et al. Aβ1–40-related reduction in functional hyperemia in mouse neocortex during somatosensory activation. Proc. Natl Acad. Sci. USA 97, 9735–9740 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Park, L. 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).
  Article CAS PubMed PubMed Central Google Scholar
• Chow, N. 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.
  Article CAS PubMed PubMed Central Google Scholar
• Bartels, A. L. 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).
  Article CAS PubMed Google Scholar
• Bartels, A. L. 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).
  Article CAS PubMed Google Scholar
• Rule, R. R., Schuff, N., Miller, R. G. & Weiner, M. W. Gray matter perfusion correlates with disease severity in ALS. Neurology 74, 821–827 (2010).
  Article PubMed PubMed Central Google Scholar
• Harris, G. J. 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).
  Article PubMed Google Scholar
• Deckel, A. W. & Duffy, J. D. Vasomotor hyporeactivity in the anterior cerebral artery during motor activation in Huntington's disease patients. Brain Res. 872, 258–261 (2000).
  Article CAS PubMed Google Scholar
• Greenberg, D. A. & Jin, K. From angiogenesis to neuropathology. Nature 438, 954–959 (2005).
  Article CAS PubMed Google Scholar
• Ruiz de Almodovar, C., Lambrechts, D., Mazzone, M. & Carmeliet, P. Role and therapeutic potential of VEGF in the nervous system. Physiol. Rev. 89, 607–648 (2009).
  Article CAS PubMed Google Scholar
• Zacchigna, S., Lambrechts, D. & Carmeliet, P. Neurovascular signalling defects in neurodegeneration. Nature Rev. Neurosci. 9, 169–181 (2008).
  Article CAS Google Scholar
• Lehtinen, M. K. et al. The cerebrospinal fluid provides a proliferative niche for neural progenitor cells. Neuron 69, 893–905 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Paris, D. et al. Impaired angiogenesis in a transgenic mouse model of cerebral amyloidosis. Neurosci. Lett. 366, 80–85 (2004).
  Article CAS PubMed Google Scholar
• Chabriat, H., Joutel, A., Dichgans, M., Tournier-Lasserve, E. & Bousser, M. G. Cadasil. Lancet Neurol. 8, 643–653 (2009).
  Article PubMed Google Scholar
• Rotstein, M. et al. Glut1 deficiency: inheritance pattern determined by haploinsufficiency. Ann. Neurol. 68, 955–958 (2010).
  Article PubMed PubMed Central Google Scholar
• Wang, D. et al. A mouse model for Glut-1 haploinsufficiency. Hum. Mol. Genet. 15, 1169–1179 (2006).
  Article CAS PubMed Google Scholar
• Eisele, Y. S. 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.
  Article CAS PubMed PubMed Central Google Scholar
• Sutcliffe, J. G., Hedlund, P. B., Thomas, E. A., Bloom, F. E. & Hilbush, B. S. Peripheral reduction of β-amyloid is sufficient to reduce brain β-amyloid: implications for Alzheimer's disease. J. Neurosci. Res. 89, 808–814 (2011).
  Article CAS PubMed Google Scholar
• Sagare, A. P., Winkler, E. A., Bell, R. D., Deane, R. & Zlokovic, B. V. From the liver to the blood–brain barrier: an interconnected system regulating brain amyloid-β levels. J. Neurosci. Res. 89, 967–968 (2011).
  Article CAS PubMed Google Scholar
• Ujiie, M., Dickstein, D. L., Carlow, D. A. & Jefferies, W. A. Blood–brain barrier permeability precedes senile plaque formation in an Alzheimer disease model. Microcirculation 10, 463–470 (2003).
  CAS PubMed Google Scholar
• Mackic, J. B. 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).
  Article CAS PubMed Google Scholar
• Mackic, J. B. 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).
  Article CAS PubMed Google Scholar
• Poduslo, J. F., Curran, G. L., Haggard, J. J., Biere, A. L. & Selkoe, D. J. 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).
  Article CAS PubMed Google Scholar
• Ghilardi, J. R. et al. Intra-arterial infusion of 125IAβ 1–40 labels amyloid deposits in the aged primate brain in vivo. Neuroreport 7, 2607–2611 (1996).
  Article CAS PubMed Google Scholar
• Zlokovic, B. V. et al. Blood–brain barrier transport of circulating Alzheimer's amyloid β. Biochem. Biophys. Res. Commun. 197, 1034–1040 (1993).
  Article CAS PubMed Google Scholar
• Martel, C. L., Mackic, J. B., McComb, J. G., Ghiso, J. & Zlokovic, B. V. 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).
  Article CAS PubMed Google Scholar
• Sagare, A. 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.
  Article CAS PubMed Google Scholar
• DeMattos, R. B., Bales, K. R., Cummins, D. J., Paul, S. M. & Holtzman, D. M. 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.
  Article CAS PubMed Google Scholar
• Sigurdsson, E. M., Scholtzova, H., Mehta, P. D., Frangione, B. & Wisniewski, T. 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).
  Article CAS PubMed PubMed Central Google Scholar
• DeMattos, R. B. 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).
  Article CAS PubMed Google Scholar
• Matsuoka, Y. 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).
  Article CAS PubMed PubMed Central Google Scholar
• Liu, Y. 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).
  Article CAS PubMed PubMed Central Google Scholar
• Liu, Y. et al. Circulating neprilysin clears brain amyloid. Mol. Cell. Neurosci. 45, 101–107 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Deane, R. 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.
  Article CAS PubMed Google Scholar
• Mackic, J. B. 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).
  Article CAS PubMed PubMed Central Google Scholar
• Giri, R. 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).
  Article CAS PubMed Google Scholar
• Yan, S. D. et al. RAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease. Nature 382, 685–691 (1996).
  Article CAS PubMed Google Scholar
• Yan, S. F., Ramasamy, R. & Schmidt, A. M. The RAGE axis: a fundamental mechanism signaling danger to the vulnerable vasculature. Circ. Res. 106, 842–853 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Mawuenyega, K. G. 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.
  Article CAS PubMed PubMed Central Google Scholar
• Zlokovic, B. V., Deane, R., Sagare, A. P., Bell, R. D. & Winkler, E. A. 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).
  Article CAS PubMed PubMed Central Google Scholar
• Deane, R. et al. LRP/amyloid β-peptide interaction mediates differential brain efflux of Aβ isoforms. Neuron 43, 333–344 (2004).
  Article CAS PubMed Google Scholar
• Shibata, M. 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.
  Article CAS PubMed PubMed Central Google Scholar
• Bell, R. D. 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).
  Article CAS PubMed Google Scholar
• Jaeger, L. B. 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).
  Article CAS PubMed PubMed Central Google Scholar
• Shinohara, M. 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).
  Article CAS PubMed PubMed Central Google Scholar
• Jaeger, L. B. 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).
  Article CAS PubMed PubMed Central Google Scholar
• Yamada, K. 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).
  Article CAS PubMed PubMed Central Google Scholar
• Nazer, B., Hong, S. & Selkoe, D. J. 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).
  Article CAS PubMed PubMed Central Google Scholar
• Monro, O. R. 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).
  Article CAS PubMed Google Scholar
• Davis, J. 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).
  Article CAS PubMed Google Scholar
• Deane, R. et al. apoE isoform-specific disruption of amyloid β peptide clearance from mouse brain. J. Clin. Invest. 118, 4002–4013 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• DeMattos, R. B. 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).
  Article CAS PubMed Google Scholar
• DeMattos, R. B. 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).
  Article CAS PubMed PubMed Central Google Scholar
• Bading, J. R. 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).
  Article CAS PubMed Google Scholar
• Donahue, J. E. et al. RAGE, LRP-1, and amyloid-β protein in Alzheimer's disease. Acta Neuropathol. 112, 405–415 (2006).
  Article CAS PubMed Google Scholar
• Cirrito, J. R. 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).
  Article CAS PubMed PubMed Central Google Scholar
• Owen, J. B. 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).
  Article CAS PubMed PubMed Central Google Scholar
• Behl, M. 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).
  Article CAS PubMed PubMed Central Google Scholar
• Sagare, A. P. 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).
  Article CAS PubMed PubMed Central Google Scholar
• Tamaki, C. 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).
  Article CAS PubMed Google Scholar
• Iwata, N. et al. Metabolic regulation of brain Aβ by neprilysin. Science 292, 1550–1552 (2001).
  Article CAS PubMed Google Scholar
• Qiu, W. Q. & Folstein, M. F. Insulin, insulin-degrading enzyme and amyloid-β peptide in Alzheimer's disease: review and hypothesis. Neurobiol. Aging 27, 190–198 (2006).
  Article CAS PubMed Google Scholar
• Melchor, J. P., Pawlak, R. & Strickland, S. The tissue plasminogen activator-plasminogen proteolytic cascade accelerates amyloid-β (Aβ) degradation and inhibits Aβ-induced neurodegeneration. J. Neurosci. 23, 8867–8871 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Yin, K. J. et al. Matrix metalloproteinases expressed by astrocytes mediate extracellular amyloid-β peptide catabolism. J. Neurosci. 26, 10939–10948 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Koistinaho, M. et al. Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-β peptides. Nature Med. 10, 719–726 (2004).
  Article CAS PubMed Google Scholar
• Bacskai, B. J. et al. Non-Fc-mediated mechanisms are involved in clearance of amyloid-β in vivo by immunotherapy. J. Neurosci. 22, 7873–7878 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Hickman, S. E., Allison, E. K. & El Khoury, J. Microglial dysfunction and defective β-amyloid clearance pathways in aging Alzheimer's disease mice. J. Neurosci. 28, 8354–8360 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Weller, R. O., Subash, M., Preston, S. D., Mazanti, I. & Carare, R. O. 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).
  Article CAS PubMed Google Scholar
• Brody, D. L. et al. Amyloid-β dynamics correlate with neurological status in the injured human brain. Science 321, 1221–1224 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Querfurth, H. W. & LaFerla, F. M. Alzheimer's disease. N.Engl. J. Med. 362, 329–344 (2010).
  Article CAS PubMed Google Scholar
• Hardy, J. The amyloid hypothesis for Alzheimer's disease: a critical reappraisal. J. Neurochem. 110, 1129–1134 (2009).
  Article CAS PubMed Google Scholar
• Lagier-Tourenne, C. & Cleveland, D. W. Neurodegeneration: an expansion in ALS genetics. Nature 466, 1052–1053 (2010).
  Article CAS PubMed Google Scholar
• Ilieva, H., Polymenidou, M. & Cleveland, D. W. Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J. Cell Biol. 187, 761–772 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Elden, A. C. et al. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466, 1069–1075 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Gruzman, A. et al. Common molecular signature in SOD1 for both sporadic and familial amyotrophic lateral sclerosis. Proc. Natl Acad. Sci. USA 104, 12524–12529 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Boillee, S. 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.
  Article CAS PubMed Google Scholar
• Yamanaka, K. et al. Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nature Neurosci. 11, 251–253 (2008).
  Article CAS PubMed Google Scholar
• Beers, D. R. 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).
  Article CAS PubMed PubMed Central Google Scholar
• Di Giorgio, F. P., Carrasco, M. A., Siao, M. C., Maniatis, T. & Eggan, K. Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nature Neurosci. 10, 608–614 (2007).
  Article CAS PubMed Google Scholar
• Nagai, M. et al. Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nature Neurosci. 10, 615–622 (2007).
  Article CAS PubMed Google Scholar
• Lambrechts, D. 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).
  Article CAS PubMed Google Scholar
• Greenway, M. J. et al. ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis. Nature Genet. 38, 411–413 (2006).
  Article CAS PubMed Google Scholar
• Oosthuyse, B. 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).
  Article CAS PubMed Google Scholar
• Mangialasche, F., Solomon, A., Winblad, B., Mecocci, P. & Kivipelto, M. Alzheimer's disease: clinical trials and drug development. Lancet Neurol. 9, 702–716 (2010).
  Article CAS PubMed Google Scholar
• Zlokovic, B. V. & Griffin, J. H. Cytoprotective protein C pathways and implications for stroke and neurological disorders. Trends Neurosci. 34, 198–209 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Storkebaum, E. et al. Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS. Nature Neurosci. 8, 85–92 (2005).
  Article CAS PubMed Google Scholar
• Azzouz, M. et al. VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature 429, 413–417 (2004).
  Article CAS PubMed Google Scholar
• US National Institutes of Health. A safety and tolerability study of intracerebroventricular administration of sNN0029 to patients with amyotrophic lateral sclerosis. ClinicalTrials.gov [online], (2011).
• Kieran, D. et al. Control of motoneuron survival by angiogenin. J. Neurosci. 28, 14056–14061 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Lopez-Lopez, C., Dietrich, M. O., Metzger, F., Loetscher, H. & Torres-Aleman, I. 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).
  Article CAS PubMed PubMed Central Google Scholar
• Spuch, C. 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).
  Article CAS PubMed Google Scholar
• Jucker, M. The benefits and limitations of animal models for translational research in neurodegenerative diseases. Nature Med. 16, 1210–1214 (2010).
  Article CAS PubMed Google Scholar
• Lo, E. H. Degeneration and repair in central nervous system disease. Nature Med. 16, 1205–1209 (2010).
  Article CAS PubMed Google Scholar
• Van Broeckhoven, C. The future of genetic research on neurodegeneration. Nature Med. 16, 1215–1217 (2010).
  Article CAS PubMed Google Scholar
• de la Torre, J. C. Vascular risk factor detection and control may prevent Alzheimer's disease. Ageing Res. Rev. 9, 218–225 (2010).
  Article CAS PubMed Google Scholar
• Luchsinger, J. A. et al. Relation of diabetes to mild cognitive impairment. Arch. Neurol. 64, 570–575 (2007).
  Article PubMed Google Scholar
• Iadecola, C. & Davisson, R. L. Hypertension and cerebrovascular dysfunction. Cell Metab. 7, 476–484 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Whitmer, R. A. et al. Central obesity and increased risk of dementia more than three decades later. Neurology 71, 1057–1064 (2008).
  Article CAS PubMed Google Scholar
• Marchesi, V. T. 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).
  Article CAS PubMed Google Scholar
• Vermeer, S. E. et al. Silent brain infarcts and the risk of dementia and cognitive decline. N. Engl. J. Med. 348, 1215–1222 (2003).
  Article PubMed Google Scholar
• Snowdon, D. A. et al. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA 277, 813–817 (1997).
  Article CAS PubMed Google Scholar
• Han, M. H. et al. Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets. Nature 451, 1076–1081 (2008).
  Article CAS PubMed Google Scholar