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. 2006 Apr 5;16(1):60–70. doi: 10.1111/j.1750-3639.2006.tb00562.x

The Role of Cystatin C in Cerebral Amyloid Angiopathy and Stroke: Cell Biology and Animal Models

Efrat Levy 1,✉, Mariusz Jaskolski 2, Anders Grubb 3
PMCID: PMC8095742  PMID: 16612983

Abstract

A variant of the cysteine protease inhibitor, cystatin c, forms amyloid deposited in the cerebral vasculature of patients with hereditary cerebral hemorrhage with amyloidosis, icelandic type (hchwa‐i), leading to cerebral hemorrhages early in life. however, cystatin c is also implicated in neuronal degenerative diseases in which it does not form the amyloid protein, such as alzheimer disease (ad). accumulating data suggest involvement of cystatin c in the pathogenic processes leading to amyloid deposition in cerebral vasculature and most significantly to cerebral hemorrhage in patients with cerebral amyloid angiopathy (caa). This review focuses on cell culture and animal models used to study the role of cystatin c in these processes.

References

  • 1.Abrahamson M, Buttle DJ, Mason RW, Hansson H, Grubb AO, Lilja H, Ohlsson K (1991) Regulation of cystatin C activity by serine proteinases. Biomed Biochim Acta 50:587–593. [PubMed] [Google Scholar]
  • 2.Abrahamson M, Grubb AO (1994) Increased body temperature accelerates aggregation of the Leu‐68‐<Gln mutant cystatin C, the amyloid‐forming protein in hereditary cystatin C amyloid angiopathy. Proc Natl Acad Sci USA 91:1416–1420. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Abrahamson M, Islam MQ, Szpirer J, Szpirer C, Levan G (1989) The human cystatin C gene (CST3), mutated in hereditary cystatin C amyloid angiopathy, is located on chromosome 20. Hum Genet 82:223–226. [DOI] [PubMed] [Google Scholar]
  • 4.Abrahamson M, Mason RW, Hansson H, Buttle DJ, Grubb AO, Ohlsson K (1991) Human cystatin C. Role of the N‐terminal segment in the inhibition of human cysteine proteinases and its inactivation by leukocyte elastase. Biochem J 273:621–626. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Abrahamson M, Olafsson I, Palsdottir A, Ulvs‐back M, Lundwall A, Jensson O, Grubb AO (1990) Structure and expression of the human cystatin C gene. Biochem J 268:287–294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Aghajanyan HG, Arzumanyan AM, Arutunyan AA, Akopyan TN (1988) Cystatins from bovine brain: purification, some properties, and action on substance P degrading activity. Neurochem Res 13:721–727. [DOI] [PubMed] [Google Scholar]
  • 7.Akopyan T (1991) Protein inhibitors of proteinases from brain. Neurochem Res 16:513–517. [DOI] [PubMed] [Google Scholar]
  • 8.Alber T (1989) Mutational effects on protein stability. Annu Rev Biochem 58:765–798. [DOI] [PubMed] [Google Scholar]
  • 9.Arnason A (1935) Apoplexie und ihre Vererbung. Acta Psychiatr Neurol Scand (Suppl) VII:1–180. [Google Scholar]
  • 10.Aronica E, van Vliet EA, Hendriksen E, Troost, D. Lopes da Silva, FH, Gorter JA (2001) Cystatin C, a cysteine protease inhibitor, is persistently up‐regulated in neurons and glia in a rat model for mesial temporal lobe epilepsy. Eur J Neurosci 14:1485–1491. [DOI] [PubMed] [Google Scholar]
  • 11.Asgeirsson B, Haebel S, Thorsteinsson L, Hel‐gason E, Gudmundsson KO, Gudmundsson G, Roepstorff P (1998) Hereditary cystatin C amyloid angiopathy: monitoring the presence of the Leu68Gln cystatin C variant in cerebrospinal fluids and monocyte cultures by MS. Biochem J 329:497–503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Assfalg‐Machleidt, I. Jochum, M. Nast‐Kolb, D. Siebeck, M. Billing, A. Joka, T. Rothe, G. Valet, G. Zauner, R. Scheuber, HP (1990) Cathepsin B‐indicator for the release of lysosomal cysteine proteinases in severe trauma and inflammation. Biol Chem Hoppe Seyler 371 Suppl:211–222. [PubMed] [Google Scholar]
  • 13.Babiloni C, Benussi L, Binetti G, Bosco P, Busonero G, Cesaretti S, Dal Forno, G, Del Percio, C, Ferri R, Frisoni G, et al (2006) Genotype (cystatin C) and EEG phenotype in Alzheimer disease and mild cognitive impairment: A multicentric study. Neuroimage 29:948–964. [DOI] [PubMed] [Google Scholar]
  • 14.Balbin M, Abrahamson M (1991) SstII polymorphic sites in the promoter region of the human cystatin C gene. Hum Genet 87:751–752. [DOI] [PubMed] [Google Scholar]
  • 15.Balbin M, Grubb AO, Abrahamson M (1993) An Ala/Thr variation in the coding region of the human cystatin C gene (CST3) detected as a SstII polymorphism. Hum Genet 92:206–207. [DOI] [PubMed] [Google Scholar]
  • 16.Benedikz E, Merz GS, Schwenk V, Johansen TE, Wisniewski HM, Rushbrook JI (1999) Cellular processing of the amyloidogenic cystatin C variant of hereditary cerebral hemorrhage with amyloidosis, Icelandic type. Amyloid 6:172–182. [DOI] [PubMed] [Google Scholar]
  • 17.Benussi L, Ghidoni R, Steinhoff T, Alberici A, Villa A, Mazzoli F, Nicosia F, Barbiero L, Broglio L, Feudatari E, et al (2003) Alzheimer disease‐associated cystatin C variant undergoes impaired secretion. Neurobiol Dis 13:15–21. [DOI] [PubMed] [Google Scholar]
  • 18.Bernstein HG, Kirschke H, Wiederanders B, Pollak KH, Zipress A, Rinne A (1996) The possible place of cathepsins and cystatins in the puzzle of Alzheimer disease: a review. Mol Chem Neuro-pathol 27:225–247. [DOI] [PubMed] [Google Scholar]
  • 19.Bever, CT, Jr.. Garver, DW (1995) Increased cathepsin B activity in multiple sclerosis brain. J Neurol Sci 131:71–73. [DOI] [PubMed] [Google Scholar]
  • 20.Beyer K, Lao JI, Gomez M, Riutort N, Latorre P, Mate JL, Ariza A (2001) Alzheimer's disease and the cystatin C gene polymorphism: an association study. Neurosci Lett 315:17–20. [DOI] [PubMed] [Google Scholar]
  • 21.Bjarnadottir M, Nilsson C, Lindstrom V, West‐man A, Davidsson P, Thormodsson F, Blondal H, Gudmundsson G, Grubb A (2001) The cerebral hemorrhage‐producing cystatin C variant (L68Q) in extracellular fluids. Amyloid 8:1–10. [DOI] [PubMed] [Google Scholar]
  • 22.Bjarnadottir M, Wulff BS, Sameni M, Sloane BF, Keppler D, Grubb A, Abrahamson M (1998) Intra‐cellular accumulation of the amyloidogenic L68Q variant of human cystatin C in NIH/3T3 cells. Mol Pathol 51:317–326. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Bobek LA, Levine MJ (1992) Cystatins‐inhibitors of cysteine proteinases. Crit Rev Oral Biol Med 3:307–332. [DOI] [PubMed] [Google Scholar]
  • 24.Booth DR, Sunde M, Bellotti V, Robinson CV, Hutchinson WL, Fraser PE, Hawkins PN, Dobson CM, Radford SE, Blake CCF, et al (1997) Instability, unfolding and aggregation of human lysozyme variants underlying amyloid fibrillogenesis. Nature 385:787–793. [DOI] [PubMed] [Google Scholar]
  • 25.Brooks WS, Kwok JB, Halliday GM, Godbolt AK, Rossor MN, Creasey H, Jones AO, Schofield PR (2004) Hemorrhage is uncommon in new Alzheimer family with Flemish amyloid precursor protein mutation. Neurology 63:1613–1617. [DOI] [PubMed] [Google Scholar]
  • 26.Bugiani O, Padovani A, Magoni M, Andora G, Sgarzi M, Savoiardo M, Bizzi A, Giaccone G, Rossi G, Tagliavini F (1998) An Italian type of HCHWA. Neurobiol Aging 19:S238. [Google Scholar]
  • 27.Burgermeister P, Calhoun ME, Winkler DT, Jucker M (2000) Mechanisms of cerebrovascular amyloid deposition. Lessons from mouse models. Ann N Y Acad Sci 903:307–316. [DOI] [PubMed] [Google Scholar]
  • 28.Burnett D, Abrahamson M, Devalia JL, Sapsford RJ, Davies RJ, Buttle DJ (1995) Synthesis and secretion of procathepsin B and cystatin C by human bronchial epithelial cells in vitro: modulation of cathepsin B activity by neutrophil elastase. Arch Biochem Biophys 317:305–310. [DOI] [PubMed] [Google Scholar]
  • 29.Buttle DJ, Abrahamson M, Burnett D, Mort JS, Barrett AJ, Dando PM, Hill SL (1991) Human sputum cathepsin B degrades proteoglycan, is inhibited by β 2‐macroglobulin and is modulated by neutrophil elastase cleavage of cathepsin B precursor and cystatin C. Biochem J 276:325–331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Calkins CC, Sloane BF (1995) Mammalian cysteine protease inhibitors: biochemical properties and possible roles in tumor progression. Biol Chem HoppeSeyler 376:71–80. [PubMed] [Google Scholar]
  • 31.Carrette, O. Burkhard, PR, Hughes S, Hochstrasser DF, Sanchez JC (2005) Truncated cystatin C in cerebrospiral fluid: Technical artefact or biological process Proteomics 5:3060–3065. [DOI] [PubMed] [Google Scholar]
  • 32.Cataldo AM, Barnett JL, Berman SA, Li J, Quar‐less S, Bursztajn S, Lippa C, Nixon RA (1995) Gene expression and cellular content of cathepsin D in Alzheimer's disease brain: evidence for early up‐regulation of the endosomal‐ lysosomal system. Neuron 14:671–680. [DOI] [PubMed] [Google Scholar]
  • 33.Cataldo AM, Hamilton DJ, Barnett JL, Paskevich PA, Nixon RA (1996) Properties of the endo‐somal‐lysosomal system in the human central nervous system: disturbances mark most neurons in populations at risk to degenerate in Alzheimer's disease. J Neurosci 16:186–199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Cathcart HM, Huang R, Lanham IS, Corder EH, Poduslo SE (2005) Cystatin C as a risk factor for Alzheimer disease. Neurology 64:755–757. [DOI] [PubMed] [Google Scholar]
  • 35.Chapman, HA, Jr.. Reilly, JJ, Jr.. Yee, R, Grubb A (1990) Identification of cystatin C, a cysteine proteinase inhibitor, as a major secretory product of human alveolar macrophages in vitro. Am Rev Respir Dis 141:698–705. [DOI] [PubMed] [Google Scholar]
  • 36.Cohen DH, Feiner H, Jensson O, Frangione B (1983) Amyloid fibril in hereditary cerebral hemorrhage with amyloidosis (HCHWA) is related to the gastroentero‐pancreatic neuroendocrine protein, β trace. J Exp Med 158:623–628. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Colon W, Kelly JW (1992) Partial denaturation of transthyretin is sufficient for amyloid fibril formation in vitro. Biochemistry 31:8654–8660. [DOI] [PubMed] [Google Scholar]
  • 38.Coria F, Castano EM, Frangione B (1987) Brain amyloid in normal aging and cerebral amyloid angiopathy is antigenically related to Alzheimer's Disease β‐protein. Am J Pathol 129:422–428. [PMC free article] [PubMed] [Google Scholar]
  • 39.Corticchiato O, Cajot J‐F, Abrahamson M, Chan SJ, Keppler D, Sordat B (1992) Cystatin C and cathepsin B in human colon carcinoma: expression by cell lines and matrix degradation. Int J Cancer 52:645–652. [DOI] [PubMed] [Google Scholar]
  • 40.Crawford FC, Freeman MJ, Schinka JA, Abdullah LI, Gold M, Hartman R, Krivian K, Morris MD, Richards D, Duara R, et al (2000) A polymorphism in the cystatin C gene is a novel risk factor for late‐onset Alzheimer's disease. Neurology 55:763–768. [DOI] [PubMed] [Google Scholar]
  • 41.Delaisse JM, Ledent P, Vaes G (1991) Colla‐genolytic cysteine proteinases of bone tissue. Cathepsin B, (pro)cathepsin Land a cathepsin L‐like 70 kDa proteinase. Biochem J 279 (Pt 1):167–174. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Deng A, Irizarry MC, Nitsch RM, Growdon JH, Rebeck GW (2001) Elevation of cystatin C in susceptible neurons in alzheimer's disease. Am J Pathol 159:1061–1068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Dodel RC, Du Y, Depboylu C, Kurz A, Eastwood B, Farlow M, Oertel WH, Muller U, Riemenschneider M (2002) A polymorphism in the cystatin C promoter region is not associated with an increased risk of AD. Neurology 58:664. [DOI] [PubMed] [Google Scholar]
  • 44.Duffy MJ (1996) Proteases as prognostic markers in cancer. Clin Cancer Res 2:613–618. [PubMed] [Google Scholar]
  • 45.Ekiel I, Abrahamson M (1996) Folding‐related dimerization of human cystatin C. J Biol Chem 271:1314–1321. [DOI] [PubMed] [Google Scholar]
  • 46.Ekiel I, Abrahamson M, Fulton DB, Lindahl P, Storer AC, Levadoux W, Lafrance M, Labelle S, Pomerleau Y, Groleau, D (1997) NMR structural studies of human cystatin C dimers and monomers. J Mol Biol 271: 266–277. [DOI] [PubMed] [Google Scholar]
  • 47.Finckh U, von Der Kammer, H, Velden J, Michel T, Andresen B, Deng A, Zhang J, Muller‐Thomsen T, Zuchowski K, Menzer G, et al (2000) Genetic association of a cystatin C gene polymorphism with late‐onset Alzheimer disease. Arch Neurol 57:1579–1583. [DOI] [PubMed] [Google Scholar]
  • 48.Gerhartz B, Abrahamson M (2002) Physicochemical properties of the N‐terminally truncated L68Q cystatin C found in amyloid deposits of brain haemorrhage patients. Biol Chem 383:301–305. [DOI] [PubMed] [Google Scholar]
  • 49.Gerhartz B, Ekiel I, Abrahamson M (1998) Two stable unfolding intermediates of the disease‐causing L68Q variant of human cystatin C. Biochemistry 37:17309–17317. [DOI] [PubMed] [Google Scholar]
  • 50.Ghiso J, Plant GT, Revesz T, Wisniewski T, Frangione B (1995) Familial cerebral amyloid angiopathy (British type) with nonneuritic amyloid plaque formation may be due to a novel amyloid protein. J Neurol Sci 129:74–75. [DOI] [PubMed] [Google Scholar]
  • 51.Ghiso J, Pons‐Estel B, Frangione B (1986) Hereditary cerebral amyloid angiopathy: the amyloid fibrils contain a protein which is a variant of cystatin C, an inhibitor of lysosomal cysteine proteases. Biochem Biophys Res Commun 136:548–554. [DOI] [PubMed] [Google Scholar]
  • 52.Glenner GG, Ein D, Eanes ED, Bladen HA, Terry W, Page DL (1971) Creation of “amyloid” fibrils from Bence Jones proteins in vitro. Science 174:712–714. [DOI] [PubMed] [Google Scholar]
  • 53.Glenner GG, Wong CW (1984) Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120:885–890. [DOI] [PubMed] [Google Scholar]
  • 54.Goddard KA, Olson JM, Payami H, Van Der Voet, M, Kuivaniemi H, Tromp G (2004) Evidence of linkage and association on chromosome 20 for late‐onset Alzheimer disease. Neurogenetics 5:121–128. [DOI] [PubMed] [Google Scholar]
  • 55.Grabowski TJ, Cho HS, Vonsattel JP, Rebeck GW, Greenberg SM (2001) Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy. Ann Neurol 49:697–705. [DOI] [PubMed] [Google Scholar]
  • 56.Graffagnino C, Herbstreith MH, Schmechel DE, Levy E, Roses AD, Alberts MJ (1995) Cystatin C mutation in an elderly man with sporadic amyloid angiopathy and intracerebral hemorrhage. Stroke 26:2190–2193. [DOI] [PubMed] [Google Scholar]
  • 57.Greenberg SM (1998) Cerebral amyloid angiopathy: prospects for clinical diagnosis and treatment. Neurology 51:690–694. [DOI] [PubMed] [Google Scholar]
  • 58.Greenberg SM, Shin Y, Grabowski TJ, Cooper GE, Rebeck GW, Iglesias S, Chapon F, Tournier‐Lasserve E, Baron JC (2003) Hemorrhagic stroke associated with the Iowa amyloid precursor protein mutation. Neurology 60:1020–1022. [DOI] [PubMed] [Google Scholar]
  • 59.Greenberg SM, Vonsattel JP, Segal AZ, Chiu RI, Clatworthy AE, Liao A, Hyman BT, Rebeck GW (1998) Association of apolipoprotein E (2 and vasculopathy in cerebral amyloid angiopathy. Neurology 50:961–965. [DOI] [PubMed] [Google Scholar]
  • 60.Grubb AO, Jensson O, Gudmundsson G, Arnason A, Lofberg H, Malm J (1984) Abnormal metabolism of β‐trace alkaline microprotein. The basic defect in hereditary cerebral hemorrhage with amyloidosis. N Engl J Med 311:1547–1549. [DOI] [PubMed] [Google Scholar]
  • 61.Gudmundsson G, Hallgrimsson J, Jonasson TA, Bjarnason O (1972) Hereditary cerebral haemorrhage with amyloidosis. Brain 95:387–404. [DOI] [PubMed] [Google Scholar]
  • 62.Haan J, Maat‐Schieman MLC, van Duinen SG, Jensson O, Thorsteinsson L, Roos RAC (1994) Co‐localization of β/A4 and cystatin C in cortical blood vessels in Dutch, but not in Icelandic hereditary cerebral hemorrhage with amyloidosis. Acta Neurol Scand 89:367–371. [DOI] [PubMed] [Google Scholar]
  • 63.Haan J, Roos RA, Algra PR, Lanser JB, Bots, GT. Vegter‐van der Vlis, M (1990) Hereditary cerebral haemorrhage with amyloidosis–Dutch type. Magnetic resonance imaging findings in 7 cases. Brain 113:1251–1267. [DOI] [PubMed] [Google Scholar]
  • 64.Hall A, Dalboge H, Grubb AO, Abrahamson M (1993) Importance of the evolutionarily conserved glycine residue in the N‐terminal region of human cystatin C (Gly‐11) for cysteine endo‐peptidase inhibition. Biochem J 291:123–129. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Hendriks L, van Duijn CM, Cras P, Cruts M, Van Hul W, van Harskamp F, Warren A, McInnis MG, Antonarakis SE, Martin JJ, et al (1992) Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the β‐amyloid precursor protein gene. Nature Genet 1:218–221. [DOI] [PubMed] [Google Scholar]
  • 66.Hendriksen H, Datson NA, Ghijsen WE, van Vliet EA, da Silva, FH, Gorter JA, Vreugdenhil E (2001) Altered hippocampal gene expression prior to the onset of spontaneous seizures in the rat post‐status epilepticus model. Eur J Neurosci 14:1475–1484. [DOI] [PubMed] [Google Scholar]
  • 67.Hochwald GM, Pepe AJ, Thorbecke GJ (1967) Trace proteins in biological fluids. IV. Physicochemical properties and sites of formation of Y trace and β trace proteins. Proc Soc Exp Med 124:961–966. [DOI] [PubMed] [Google Scholar]
  • 68.Hoffmann MC, Nitsch C, Scotti AL, Reinhard E, Monard D (1992) The prolonged presence of glia‐derived nexin, an endogenous protease inhibitor, in the hippocampus after ischemia‐induced delayed neuronal death. Neuroscience 49:397–408. [DOI] [PubMed] [Google Scholar]
  • 69.Hurle MR, Helms LR, Li L, Chan W, Wetzel R (1994) A role for destabilizing amino acid replacements in light‐chain amyloidosis. Proc Natl Acad Sci USA 91:5446–5450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Ishimaru H, Ishikawa K, Ohe Y, Takahashi A, Maruyama Y (1996) Cystatin C and apolipoprotein E immunoreactivities in CA1 neurons in ischemic gerbil hippocampus. Brain Res 709:155–162. [DOI] [PubMed] [Google Scholar]
  • 71.Itoh Y, Yamada M, Hayakawa M, Otomo E, Miyatake T (1993) Cerebral amyloid angiopathy: a significant cause of cerebellar as well as lobar cerebral hemorrhage in the elderly. J Neurol Sci 116:135–141. [DOI] [PubMed] [Google Scholar]
  • 72.Izumihara A, Ishihara T, Hoshii Y, Ito H (2001) Cerebral amyloid angiopathy associated with hemorrhage: immunohistochemical study of 41 biopsy cases. Neurol Med Chir (Tokyo) 41:471–477; discussion 477–478. [DOI] [PubMed] [Google Scholar]
  • 73.Janowski R, Abrahamson M, Grubb A, Jaskolski M (2004) Domain swapping in N‐truncated human cystatin C. J Mol Biol 341:151–160. [DOI] [PubMed] [Google Scholar]
  • 74.Janowski R, Kozak M, Abrahamson M, Grubb A, Jaskolski M (2005) 3D Domain‐swapped human cystatin C with amyloidlike intermolecular β‐sheets. Structure Function, and Bioinformatics 61:570–578. [DOI] [PubMed] [Google Scholar]
  • 75.Janowski R, Kozak M, Jankowska E, Grzonka Z, Grubb A, Abrahamson M, Jaskolski M (2001) Human cystatin C, an amyloidogenic protein, dimerizes through three‐dimensional domain swapping. Nat Struct Biol 8:316–320. [DOI] [PubMed] [Google Scholar]
  • 76.Jaskolski M (2001) 3D domain swapping, protein oligomerization, and amyloid formation. Acta Biochim Pol 48:807–827. [PubMed] [Google Scholar]
  • 77.Jelic, V. Julin, P, Shigeta M, Nordberg A, Lannfelt L, Winblad B, Wahlund LO (1997) Apolipoprotein E ?4 allele decreases functional connectivity in Alzheimer's disease as measured by EEG coherence. J Neurol Neurosurg Psychiatry 63:59–65. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Jellinger K (1977) Cerebrovascular amyloidosis with cerebral hemorrhage. J Neurol 214:195–206. [DOI] [PubMed] [Google Scholar]
  • 79.Johansen TE, Vogel CK, Schwartz TW (1990) C‐terminal KDEL‐modified cystatin C is retained in transfected CHO cells. Biochem Biophys Res Commun 172:1384–1391. [DOI] [PubMed] [Google Scholar]
  • 80.Kabanda A, Goffin E, Bernard A, Lauwerys R, van Ypersele de Strihou, C (1995) Factors influencing serum levels and peritoneal clearances of low molecular weight proteins in continuous ambulatory peritoneal dialysis. Kidney Int 48:1946–1952. [DOI] [PubMed] [Google Scholar]
  • 81.Kamino K, Orr HT, Payami H, Wijsman EM, Alonso ME, Pulst SM, Anderson L, O'Dahl S, Nemens E, White, J A (1992) Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region. Am J Hum Genet 51:998–1014. [PMC free article] [PubMed] [Google Scholar]
  • 82.Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, Mueller‐Hill B (1987) The precursor of Alzheimer's disease amyloid A4 protein resembles a cell‐surface receptor. Nature 325:733–736. [DOI] [PubMed] [Google Scholar]
  • 83.Katakai K, Shinoda M, Kabeya K, Watanabe M, Ohe, Y. Mori, M, Ishikawa K (1997) Changes in distribution of cystatin C, apolipoprotein E and fer‐ritin in rat hypothalamus after hypophysectomy. J Neuroendocrinol 9:247–253. [DOI] [PubMed] [Google Scholar]
  • 84.Kawai M, Kalaria RN, Cras P, Siedlak SL, Velasco ME, Shelton ER, Chan HW, Greenberg BD, Perry G (1993) Degeneration of vascular muscle cells in cerebral amyloid angiopathy of Alzheimer disease. Brain Res 623:142–146. [DOI] [PubMed] [Google Scholar]
  • 85.Kiuru S, Salonen O, Haltia M (1999) Gelsolin‐related spinal and cerebral amyloid angiopathy. AnnNeuro l45:305–311. [DOI] [PubMed] [Google Scholar]
  • 86.Kiuru‐Enari S, Somer H, Seppalainen AM, Not‐kola IL, Haltia M (2002) Neuromuscular pathology in hereditary gelsolin amyloidosis. JNeuropathol Exp Neurol 61:565–571. [DOI] [PubMed] [Google Scholar]
  • 87.Lah, TT. Babnik, J, Schiffmann E, Turk, V. Skaleric, U (1993) Cysteine proteinases and inhibitors in inflammation: their role in periodontal disease. J Periodon 64:485–491. [PubMed] [Google Scholar]
  • 88.LeBlanc A (1995) Increased production of 4 kDa amyloid β peptide in serum deprived human primary neuron cultures: possible involvement of apoptosis. J Neurosci 15:7837–7846. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89.Lee KS, Frank S, Vanderklish P, Arai A, Lynch G (1991) Inhibition of proteolysis protects hippo‐campal neurons from ischemia. Proc Natl Acad Sci USA 88:7233–7237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90.Lehtovirta M, Partanen J, Kononen M, Hil‐tunen J, Helisalmi S, Hartikainen P, Riekkinen, P, Jr.. Soininen, H (2000) A longitudinal quantitative EEG study of Alzheimer's disease: relation to apolipoprotein E polymorphism. Dement Geriatr Cogn Disord 11:29–35. [DOI] [PubMed] [Google Scholar]
  • 91.Lehtovirta M, Partanen J, Kononen M, Soininen H, Helisalmi S, Mannermaa A, Ryynanen M, Hartikainen P, Riekkinen, P, Jr. (1996) Spectral analysis of EEG in Alzheimer's disease: relation to apolipoprotein E polymorphism. NeurobiolAging 17:523–526. [DOI] [PubMed] [Google Scholar]
  • 92.Lenarcic B, Krasovec M, Ritonja A, Olafsson I, Turk V (1991) Inactivation of human cystatin C and kininogen by human cathepsin D. FEBS Letters 280:211–215. [DOI] [PubMed] [Google Scholar]
  • 93.Levy E, Amorim A, Frangione B, Walker LC (1995) β‐amyloid precursor protein gene in squirrel monkeys with cerebral amyloid angiopathy. Neurobiol Aging 16:805–808. [DOI] [PubMed] [Google Scholar]
  • 94.Levy E, Carman MD, Fernandez‐Madrid IJ, Power MD, Lieberburg I, van Duinen SG, Bots GTAM, Luyendijk W, Frangione B (1990) Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 248:1124–1126. [DOI] [PubMed] [Google Scholar]
  • 95.Levy E, Lopez‐Otin C, Ghiso J, Geltner D, Frangione B (1989) Stroke in Icelandic patients with hereditary amyloid angiopathy is related to a mutation in the cystatin C gene, an inhibitor of cysteine proteases. J Exp Med 169:1771–1778. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 96.Levy E, Sastre M, Kumar A, Gallo G, Piccardo P, Ghetti B, Tagliavini F (2001) Codeposition of cystatin C with amyloid‐β protein in the brain of Alzheimer's disease patients. J Neuropathol Exp Neurol 60:94–104. [DOI] [PubMed] [Google Scholar]
  • 97.Lin C, Wang ST, Wu CW, Chuo LJ, Kuo YM (2003) The association of a cystatin C gene polymorphism with late‐onset Alzheimer's disease and vascular dementia. Chin J Physiol 46:111–115. [PubMed] [Google Scholar]
  • 98.Lindahl P, Ripoll D, Abrahamson M, Mort JS, Storer AC (1994) Evidence for the interaction of valine‐10 in cystatin C with the S2 subsite of cathepsin B. Biochemistry 33:4384–4392. [DOI] [PubMed] [Google Scholar]
  • 99.Lofberg H, Grubb AO, Nilsson EK, Jensson O, Gudmundsson G, Blondal H, Arnason A, Thor‐steinsson L (1987) Immunohistochemical characterization of the amyloid deposits and quantita‐tion of pertinent cerebrospinal fluid proteins in hereditary cerebral hemorrhage with amyloidosis. Stroke 18:431–440. [DOI] [PubMed] [Google Scholar]
  • 100.Lukasiuk K, Pirttila TJ, Pitkanen A (2002) Upregulation of cystatin C expression in the rat hippocampus during epileptogenesis in the amygdala stimulation model of temporal lobe epilepsy. Epilepsia 43 Suppl 5:137–145. [DOI] [PubMed] [Google Scholar]
  • 101.Lundgren E, Persson H, Andersson K, Olofsson A, Dacklin I, Goldsteins G (1999) Mapping protein conformations in fibril structures using monoclonal antibodies. Methods Enzymol 309:591–605. [DOI] [PubMed] [Google Scholar]
  • 102.Luyendijk W, Bots, GT. Vegter‐van der Vlis, M, Went LN, Frangione B (1988) Hereditary cerebral haemorrhage caused by cortical amyloid angiopathy. J Neurol Sci 85:267–280. [DOI] [PubMed] [Google Scholar]
  • 103.Maruyama H, Izumi Y, Oda M, Torii T, Morino H, Toji H, Sasaki K, Terasawa H, Nakamura S, Kawakami H (2001) Lack of an association between cystatin C gene polymorphisms in Japanese patients with Alzheimer's disease. Neurology 57:337–339. [DOI] [PubMed] [Google Scholar]
  • 104.Maruyama K, Ikeda S, Ishihara T, Allsop D, Yanagisawa N (1990) Immunohistochemical characterization of cerebrovascular amyloid in 46 autopsied cases using antibodies to β protein and cystatin C. Stroke 21:397–403. [DOI] [PubMed] [Google Scholar]
  • 105.Maruyama K, Kametani F, Ikeda S, Ishihara T, Yanagisawa N (1992) Characterization of amyloid fibril protein from a case of CAA showing immunohistochemical reactivity for both β protein and cystatin C. Neurosci Lett 144:38–42. [DOI] [PubMed] [Google Scholar]
  • 106.Mastaglia FL, Byrnes ML, Johnsen RD, Kakulas BA (2003) Prevalence of cerebral vascular amyloid‐β deposition and stroke in an aging Australian population: a postmortem study. J Clin Neurosci 10:186–189. [DOI] [PubMed] [Google Scholar]
  • 107.Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K (1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A 82:4245–4249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 108.McCarron MO, Nicoll JA, Stewart J, Cole GM, Yang F, Ironside JW, Mann DM, Love S, Graham DI (2000) Amyloid β‐protein length and cerebral amyloid angiopathy‐related haemorrhage. Neuroreport 11:937–940. [DOI] [PubMed] [Google Scholar]
  • 109.McCarron MO, Nicoll JA, Stewart J, Ironside JW, Mann DM, Love S, Graham DI, Dewar D (1999) The apolipoprotein E ?2 allele and the pathological features in cerebral amyloid angiopathy‐related hemorrhage. J Neuropathol Exp Neurol 58:711–718. [DOI] [PubMed] [Google Scholar]
  • 110.McCarron MO, Nicoll JA, Stewart J, Ironside JW, Mann DM, Love S, Graham DI, Grubb A (2000) Absence of cystatin C mutation in sporadic cerebral amyloid angiopathy‐related hemorrhage. Neurology 54:242–244. [DOI] [PubMed] [Google Scholar]
  • 111.McCutchen SL, Lai Z, Miroy GJ, Kelly JW, Colon W (1995) Comparison of lethal and nonlethal transthyretin variants and their relationship to amyloid disease. Biochemistry 34:13527–13536. [DOI] [PubMed] [Google Scholar]
  • 112.Merz GS, Benedikz E, Schwenk V, Johansen TE, Vogel LK, Rushbrook JI, Wisniewski HM (1997) Human cystatin C forms an inactive dimer during intracellular trafficking in transfected CHO cells. J Cell Physiol 173:423–432. [DOI] [PubMed] [Google Scholar]
  • 113.Miyake T, Gahara Y, Nakayama M, Yamada H, Uwabe K, Kitamura T (1996) Up‐regulation of cystatin C by microglia in the rat facial nucleus following axotomy. Mol Brain Res 37:273–282. [DOI] [PubMed] [Google Scholar]
  • 114.Morelli L, Wei L, Amorim A, McDermid J, Abee CR, Frangione B, Walker LC, Levy E (1996) Cerebrovascular amyloidosis in squirrel monkeys and rhesus monkeys: apolipoprtein E genotype. FEBS Letters 379:132–134. [DOI] [PubMed] [Google Scholar]
  • 115.Nagai A, Kobayashi S, Shimode K, Imaoka K, Umegae N, Fujihara S, Nakamura M (1998) No mutations in cystatin C gene in cerebral amyloid angiopathy with cystatin C deposition. Mol Chem Neuropathol 33:63–78. [DOI] [PubMed] [Google Scholar]
  • 116.Nakamura Y, Takeda M, Suzuki H, Hattori H, Tada K, Hariguchi S, Hashimoto S, Nishimura T (1991) Abnormal distribution of cathepsins in the brain of patients with Alzheimer's disease. Neurosci Lett 130:195–198. [DOI] [PubMed] [Google Scholar]
  • 117.Nicoll JA, Burnett C, Love S, Graham DI, Dewar, D. I. Ronside, J W, Stewart J, Vinters HV (1997) High frequency of apolipoprotein E ɛ2 allele in hemorrhage due to cerebral amyloid angiopathy. Ann Neurol 41:716–721. [DOI] [PubMed] [Google Scholar]
  • 118.Nicoll JA, Burnett C, Love S, Graham DI, Ironside J W, Vinters HV (1996) High frequency of apolipoprotein E ?2 in patients with cerebral hemorrhage due to cerebral amyloid angiopathy. Ann Neurol 39:682–683. [DOI] [PubMed] [Google Scholar]
  • 119.Nilsson M, Wang X, Rodziewicz‐Motowidlo S, Janowski R, Lindstrom V, Onnerfjord P, Wester‐mark G, Grzonka Z, Jaskolski M, Grubb A (2004) Prevention of domain swapping inhibits dimerization and amyloid fibril formation of cystatin C: use of engineered disulfide bridges, antibodies, and carboxymethylpapain to stabilize the monomeric form of cystatin C. J Biol Chem 279:24236–24245. [DOI] [PubMed] [Google Scholar]
  • 120.Nishio C, Yoshida K, Nishiyama K, Hatanaka H, Yamada M (2000) Involvement of cystatin C in oxidative stress‐induced apoptosis of cultured rat CNS neurons. Brain Res 873:252–262. [DOI] [PubMed] [Google Scholar]
  • 121.Nishiyama K, Konishi A, Nishio C, Araki‐Yoshida K, Hatanaka H, Kojima M, Ohmiya Y, Yamada M, Koshimizu H (2005) Expression of cystatin C prevents oxidative stress‐induced death in PC12 cells. Brain Res Bull 67:94–99. [DOI] [PubMed] [Google Scholar]
  • 122.Nitatori T, Sato N, Waguri S, Karasawa Y, Araki H, Shibanai K, Kominami E, Uchiyama Y (1995) Delayed neuronal death in the CA1 pyramidal cell layer of the gerbil hippocampus following transient ischemia is apoptosis. J Neurosci 15:1001–1011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 123.Noto D, Cefalu AB, Barbagallo CM, Pace A, Rizzo M, Marino G, Caldarella R, Castello A, Per‐nice V, Notarbartolo A, et al (2005) Cystatin C levels are decreased in acute myocardial infarction: effect of cystatin C G73A gene polymorphism on plasma levels. Int J Cardiol 101:213–217. [DOI] [PubMed] [Google Scholar]
  • 124.Obici L, Demarchi A, de Rosa G, Bellotti V, Marciano S, Donadei S, Arbustini E, Palladini G, Diegoli M, Genovese E, et al (2005) A novel A?PP mutation exclusively associated with cerebral amyloid angiopathy. Ann Neurol 58:639–644. [DOI] [PubMed] [Google Scholar]
  • 125.Olafsson I, Gudmundsson G, Abrahamson M, Jensson O, Grubb AO (1990) The amino terminal portion of cerebrospinal fluid cystatin C in hereditary cystatin C amyloid angiopathy is not truncated: direct sequence analysis from aga‐rose gel electropherograms. Scan J Clin Lab Invest 50:85–93. [DOI] [PubMed] [Google Scholar]
  • 126.Olafsson I, Thorsteinsson L, Jensson O (1996) The molecular pathology of hereditary cystatin C amyloid angiopathy causing brain hemorrhage. Brain Pathol 6:121–126. [DOI] [PubMed] [Google Scholar]
  • 127.Olson JM, Goddard KA, Dudek DM (2002) A second locus for very‐late‐onset Alzheimer disease: a genome scan reveals linkage to 20p and epistasis between 20p and the amyloid precursor protein region. Am J Hum Genet 71:154–161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 128.Pakula AA, Sauer RT (1989) Genetic analysis of protein stability and function. Ann Rev Genet 23:289–310. [DOI] [PubMed] [Google Scholar]
  • 129.Palm DE, Knuckey NW, Primiano MJ, Spangenberger AG, Johanson CE (1995) Cystatin C, a protease inhibitor, in degenerating rat hippo‐campal neurons following transient forebrain ischemia. Brain Res 691:1–8. [DOI] [PubMed] [Google Scholar]
  • 130.Palsdottir A, Abrahamson M, Thorsteinsson L, Arnason A, Olafsson I, Grubb AO, Jensson O (1988) Mutation in cystatin C gene causes hereditary brain haemorrhage. Lancet 2:603–604. [DOI] [PubMed] [Google Scholar]
  • 131.Paraoan L, Ratnayaka A, Spiller DG, Hiscott P, White MR, Grierson I (2004) Unexpected intracellular localization of the AMD‐associated cystatin C variant. Traffic 5:884–895. [DOI] [PubMed] [Google Scholar]
  • 132.Parfitt M, Crook R, Roques P, Rossor M, Chartier‐Harlin MC (1993) The cystatin‐C gene is not linked to early onset familial Alzheimer's disease. Neurosci Lett 154:81–83. [DOI] [PubMed] [Google Scholar]
  • 133.Pawlik, M. Danilov, V. Mancevska, K, Morbin M, Tagliavini F, Levy E. (2002) Hemorrhages caused by overexpression of cystatin C in transgenic mice. Neurobiol Aging 23:S242. [Google Scholar]
  • 134.Pawlik M, Sastre M, Calero M, Mathews PM, Schmidt SD, Nixon RA, Levy E (2004) Overexpression of human cystatin C in transgenic mice does not affect levels of endogenous brain amyloid β peptide. J Mol Neurosci 22:13–18. [DOI] [PubMed] [Google Scholar]
  • 135.Peppard JV, Knap AK (1999) Effect of the selective and non‐selective cysteine protease inhibitors on the intracellular processing of interleukin 6 by HEPG2 cells. In Vitro Cell Dev Biol Anim 35:459–464. [DOI] [PubMed] [Google Scholar]
  • 136.Poduri A, Gearing M, Rebeck GW, Mirra SS, Tigges J, Hyman BT (1994) Apolipoprotein E4 and (3 amyloid in senile plaques and cerebral blood vessels of aged Rhesus monkeys. Am J Pathol 144:1183–1187. [PMC free article] [PubMed] [Google Scholar]
  • 137.Price DL, Martin LJ, Sisodia SS, Walker LC, Voytko ML, Wagster MV, Cork LC, Koliatsos VE (1994) The aged nonhuman primate. A model for the behavioral and brain abnormalities occurring in aged humans. In: Alzheimer's disease, Terry RD. Katzman R. Blick KL (eds). Raven Press: New York , pp. 231–245. [Google Scholar]
  • 138.Rider BJ, Fraga E, Yu Q, Singh B (1996) Immune responses to self peptides naturally presented by murine class II major histocompatibility complex molecules. Mol Immunol 33:625–633. [DOI] [PubMed] [Google Scholar]
  • 139.Roberts‐Lewis JM, Marcy VR, Zhao Y, Vaught JL, Siman R, Lewis ME (1993) Aurintricarboxylic acid protects hippocampal neurons from NMDA‐and ischemia‐induced toxicity in vivo. J Neurochem 61:378–381. [DOI] [PubMed] [Google Scholar]
  • 140.Roks G, Cruts M, Slooter AJ, Dermaut B, Hofman A, van Broeckhoven C, van Duijn CM (2001) The cystatin C polymorphism is not associated with early onset Alzheimer's disease. Neurology 57:366–367. [DOI] [PubMed] [Google Scholar]
  • 141.Rosand J, Hylek EM, O'Donnell HC, Green‐berg SM (2000) Warfarin‐associated hemorrhage and cerebral amyloid angiopathy: a genetic and pathologic study. Neurology 55:947–951. [DOI] [PubMed] [Google Scholar]
  • 142.Rozemuller AJ, Roos RA, Bots GT, Kamphorst W, Eikelenboom P, van Nostrand WE (1993) Distribution of β/A4 protein and amyloid precursor protein in hereditary cerebral hemorrhage with amyloidosis‐Dutch type and Alzheimer's disease. Am J Pathol 142:1449–1457. [PMC free article] [PubMed] [Google Scholar]
  • 143.Rudensky A, Preston‐Hurlburt P, Hong SC, Barlow A, Janeway, CA, Jr. (1991) Sequence analysis of peptides bound to MHC class II molecules. Nature 353:622–627. [DOI] [PubMed] [Google Scholar]
  • 144.Saitoh E, Sabatini LM, Eddy RL, Shows TB, Azen EA, Isemura S, Sanada K (1989) The human cystatin C gene (CST3) is a member of the cystatin gene family which is localized on chromosome 20. Biochem Biophys Res Commun 162:1324–1331. [DOI] [PubMed] [Google Scholar]
  • 145.Sastre M, Calero M, Pawlik M, Mathews PM, Kumar A, Danilov, V. Schmidt, SD, Nixon RA, Fran‐gione B, Levy E (2004) Binding of cystatin C to Alzheimer's amyloid β inhibits amyloid fibril formation. Neurobiol Aging 25:1033–1043. [DOI] [PubMed] [Google Scholar]
  • 146.Schmechel DE, Saunders AM, Strittmatter WJ, Crain BJ, Hulette CM, Joo SH, Pericak‐Vance MA, Goldgaber D, Roses AD (1993) Increased amyloid β‐peptide deposition in cerebral cortex as a concequence of apolipoprotein E genotype in late‐onset Alzheimer's disease. Proc Natl Acad Sci USA 90:9649–9653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 147.Shirahama T, Cohen AS (1975) Intralyso‐somal formation of amyloid fibrils. Am J Pathol 81:101–116. [PMC free article] [PubMed] [Google Scholar]
  • 148.Sohar I, Laszlo A, Gaal K, Mechler F (1988) Cysteine and metalloproteinase activities in serum of Duchenne muscular dystrophic genotypes. Biol Chem Hoppe Seyler 369 Suppl:277–279. [PubMed] [Google Scholar]
  • 149.Steinhoff T, Moritz E, Wollmer MA, Mohajeri MH, Kins S, Nitsch RM (2001) Increased cystatin C in astrocytes of transgenic mice expressing the K670N‐M671L mutation of the amyloid precursor protein and deposition in brain amyloid plaques. Neurobiol Dis 8:647–654. [DOI] [PubMed] [Google Scholar]
  • 150.Sun Q (1989) Growth stimulation of 3T3 fibroblasts by cystatin. Exp Cell Res 180:150–160. [DOI] [PubMed] [Google Scholar]
  • 151.Tanzi RE, Bertram L (2001) New frontiers in Alzheimer's disease genetics. Neuron 32:181–184. [DOI] [PubMed] [Google Scholar]
  • 152.Tanzi RE, Vaula G, Romano DM, Mortilla M, Huang TL, Tupler RG, Wasco W, Hyman BT, Haines JL, Jenkins BJ, et al (1992) Assessment of amyloid β‐protein precursor gene mutations in a large set of familial and sporadic Alzheimer disease cases. Am J Hum Gen 51:273–282. [PMC free article] [PubMed] [Google Scholar]
  • 153.Taupin P, Ray J, Fischer WH, Suhr ST, Hakansson K, Grubb A, Gage FH (2000) FGF‐2–Responsive neural stem cell proliferation requires CCg, a novel Autocrine/Paracrine cofactor. Neuron 28:385–397. [DOI] [PubMed] [Google Scholar]
  • 154.Thomssen C, Schmitt M, Goretzki L, Oppelt P, Pache L, Dettmar P, Janicke F, Graeff H (1995) Prognostic value of the cysteine proteases cathepsins B and cathepsin L in human breast cancer. Clin Cancer Res 1:741–746. [PubMed] [Google Scholar]
  • 155.Thorsteinsson L, Georgsson G, Asgeirsson B, Bjarnadottir M, Olafsson I, Jensson O, Gudmundsson G (1992) On the role of monocytes/macrophages in the pathogenesis of central nervous system lesions in hereditary cystatin C amyloid angiopathy. J Neurol Sci 108:121–128. [DOI] [PubMed] [Google Scholar]
  • 156.Tizon B, Levy E (2006) Protease inhibitors and their involvement in neurological disorders. In: Handbook of Neurochemistry and Molecular Neurobiology, Lajtha A (eds). Springer Publishers: New York , vol 7. [Google Scholar]
  • 157.Trabandt A, Gay RE, Fassbender HG, Gay S (1991) Cathepsin B in synovial cells at the site of joint destruction in rheumatoid arthritis. Arthritis Rheum 34:1444–1451. [DOI] [PubMed] [Google Scholar]
  • 158.Tsuchiya K, Kohda Y, Yoshida M, Zhao L, Ueno T, Yamashita J, Yoshioka T, Kominami E, Yamashima T (1999) Postictal blockade of ischemic hippocampal neuronal death in primates using selective cathepsin inhibitors. Exp Neurol 155:187–194. [DOI] [PubMed] [Google Scholar]
  • 159.Turk B, Turk D, Turk V (2000) Lysosomal cysteine proteases: more than scavengers. Biochim Biophys Acta 1477:98–111. [DOI] [PubMed] [Google Scholar]
  • 160.Uchida K, Kuroki K, Yoshino T, Yamaguchi R, Tateyama S (1997) Immunohistochemical study of constituents other than β‐protein in canine senile plaques and cerebral amyloid angiopathy. Acta Neuropathol (Berl) 93:277–284. [DOI] [PubMed] [Google Scholar]
  • 161.Uchida K, Nakayama H, Tateyama S, Goto N (1992) Immunohistochemical analysis of constituents of senile plaques and cerebro‐vascular amyloid in aged dogs. J Veter Med Sci 54:1023–1029. [DOI] [PubMed] [Google Scholar]
  • 162.van Duinen SG, Castano EM, Prelli F, Bots GT, Luyendijk W, Frangione B (1987) Hereditary cerebral hemorrhage with amyloidosis in patients of Dutch origin is related to Alzheimer disease. Proc Natl Acad Sci U S A 84:5991–5994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 163.Vattemi G, Engel WK, McFerrin J, Askanas V (2003) Cystatin C colocalizes with amyloid‐β and coimmunoprecipitates with amyloid‐β precursor protein in sporadic inclusion‐body myositis muscles. J Neurochem 85:1539–1546. [DOI] [PubMed] [Google Scholar]
  • 164.Vinters HV (1987) Cerebral amyloid angiopathy. A critical review. Stroke 18:311–324. [DOI] [PubMed] [Google Scholar]
  • 165.Vinters HV (2001) Cerebral amyloid angiopathy: a microvascular link between parenchymal and vascular dementia Ann Neurol 49:691–693. [DOI] [PubMed] [Google Scholar]
  • 166.Vinters HV, Gilbert JJ (1983) Cerebral amyloid angiopathy: incidence and complications in the aging brain. II. The distribution of amyloid vascular changes. Stroke 14:924–928. [DOI] [PubMed] [Google Scholar]
  • 167.Vinters HV, Nishimura GS, Secor DL, Pardridge WM (1990) Immunoreactive A4 and β‐trace peptide colocalization in amyloidotic arteriolar lesions in brains of patients with Alzheimer's disease. Am J Pathol 137:233–240. [PMC free article] [PubMed] [Google Scholar]
  • 168.Vonsattel JP, Myers RH, Hedley‐Whyte ET, Ropper AH, Bird ED, Richardson, EP, Jr. (1991) Cerebral amyloid angiopathy without and with cerebral hemorrhages: a comparative histological study. Ann Neurol 30:637–649. [DOI] [PubMed] [Google Scholar]
  • 169.Walker LC, Masters C, Beyreuther K, Price DL (1990) Amyloid in the brains of aged squirrel monkeys. Acta Neuropathol 80:381–387. [DOI] [PubMed] [Google Scholar]
  • 170.Wang Z, Wu D, Vinters HV (2002) Hypoxia and reoxygenation of brain microvascular smooth muscle cells in vitro: cellular responses and expression of cerebral amyloid angiopathy‐associated proteins. Apmis 110:423–434. [DOI] [PubMed] [Google Scholar]
  • 171.Wattendorff AR, Bots GT, Went LN, Endtz LJ (1982) Familial cerebral amyloid angiopathy presenting as recurrent cerebral hemorrhage. J Neurol Sci 55:121–135. [DOI] [PubMed] [Google Scholar]
  • 172.Wei L, Berman Y, Castano EM, Cadene M, Beavis RC, Devi L, Levy E (1998) Instability of the amyloidogenic cystatin C variant of hereditary cerebral hemorrhage with amyloidosis, Icelandic type. J Biol Chem 273:11806–11814. [DOI] [PubMed] [Google Scholar]
  • 173.Wei L, Walker LC, Levy E (1996) Cystatin C: Icelandic‐like mutation in an animal model of cerebrovascular β amyloidosis. Stroke 27:2080–2085. [DOI] [PubMed] [Google Scholar]
  • 174.Winkler DT, Bondolfi L, Herzig MC, Jann L, Calhoun ME, Wiederhold KH, Tolnay M, Staufeniel M, Jucker M (2001) Spontaneous hemorrhagic stroke in a mouse model of cerebral amyloid angiopathy. J Neurosci 21:1619–1627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 175.Wisniewski HM, Terry RD (1973) Morphology of the aging brain, human and animal. Prog Brain Res 40:167–186. [DOI] [PubMed] [Google Scholar]
  • 176.Wisniewski T, Ghiso J, Frangione B (1991) Peptides homologous to the amyloid protein of Alzheimer's disease containing a glutamine for glutamic acid substitution have accelerated amyloid fibril formation. Biochem Biophys Res Com-mun 179:1247–1254. [DOI] [PubMed] [Google Scholar]
  • 177.Woo D, Sauerbeck LR, Kissela BM, Khoury JC, Szaflarski JP, Gebel J, Shukla R, Pancioli AM, Jauch EC, Menon AG, et al (2002) Genetic and environmental risk factors for intracerebral hemorrhage: preliminary results of a population‐based study. Stroke 33:1190–1195. [DOI] [PubMed] [Google Scholar]
  • 178.Yamada M (2000) Cerebral amyloid angiopathy: an overview. Neuropathology 20:8–22. [DOI] [PubMed] [Google Scholar]
  • 179.Yamada M (2002) Risk factors for cerebral amyloid angiopathy in the elderly. Ann N Y Acad Sci 977:37–44. [DOI] [PubMed] [Google Scholar]
  • 180.Yamashima T, Kohda Y, Tsuchiya K, Ueno T, Yamashita J, Yoshioka T, Kominami E (1998) Inhibition of ischaemic hippocampal neuronal death in primates with cathepsin B inhibitor CA‐074: a novel strategy for neuroprotection based on 'calpain‐cathepsin hypothesis'. Eur J Neurosci 10:1723–1733. [DOI] [PubMed] [Google Scholar]
  • 181.Ying GX, Huang C, Jiang ZH, Liu X, Jing NH, Zhou CF (2002) Up‐regulation of cystatin C expression in the murine hippocampus following perforant path transections. Neuroscience 112:289–298. [DOI] [PubMed] [Google Scholar]
  • 182.Zannis VI, Nicolosi RJ, Jensen E, Breslow JL, Hayes KC (1985) Plasma and hepatic apoE isoproteins of nonhuman primates. Differences in apoE among humans, apes, and New and Old World monkeys. J Lipid Res 26:1421–1430. [PubMed] [Google Scholar]

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