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  • Print publication year: 2005
  • Online publication date: August 2010

29 - The neuropathology of Alzheimer's disease in the year 2005

from Part IV - Alzheimer's disease



The current molecular era of the neuropathology of Alzheimer's disease began in the early 1970s with the first attempts to characterize the biochemical basis of the amyloid deposits (now designated Aβ), which remain the pathognomic feature of this illness (Nikaido et al., 1971). Subsequent dramatic progress in amino acid sequencing (Glenner & Wong, 1984; Masters et al., 1985), gene cloning (Kang et al., 1987), and elucidation of the biogenesis of the Aβ amyloid protein (for recent reviews see Beyreuther et al., 2001; Cummings & Cole, 2002; Hardy & Selkoe, 2002; Ines Dominguez & DeStrooper, 2002; McLean et al., 2001; Sisodia & St George-Hyslop, 2002) have led to a coherent picture of the pathogenesis of AD. However, this explosion of knowledge on AD still has not been fully translated back into the clinic, the pathology laboratory, or the mortuary, where diagnostic criteria remain subjective and ambiguous. As the natural history of AD becomes better understood at the molecular level, it would be highly desirable to develop standardized protocols for diagnosis based around the principal biochemical pathway: the biogenesis and accumulation of Aβ amyloid in susceptible areas of the brain (Fig. 29.1). This chapter outlines the traditional methods of neuropathologic diagnosis, together with some approaches to the contemporary molecular diagnosis of AD both during life and after death (Fig. 29.2), which should have general applicability to the other major diseases caused by the toxic gains-of-function of α-synuclein (Parkinson's disease; diffuse Lewy body disease; multiple system atrophy), prion protein (Creutzfeldt–Jakob and related diseases); Cu–Zu superoxide dismutase (amyotrophic lateral sclerosis); polyglutamine expansions (Huntington's disease and mechanistically related illnesses) and the tau microtubule associated protein (frontotemporal degenerations; Pick's disease; cortico-basal degeneration; progressive supranuclear palsy).

Andreasen, N., Minthon, L., Davidsson, al. (2001a). Evaluation of CSF-tau and CSF-Aβ42 as diagnostic markers for Alzheimer disease in clinical practice. Arch. Neurol., 58, 373–9
Andreasen, N., Gottfries, J., Vanmechelen, al. (2001b). Evaluation of CSF biomarkers for axonal and neuronal degeneration, gliosis, and β-amyloid metabolism in Alzheimer's disease. J. Neurol. Neurosurg. Psychiatr., 71, 557–8
Bading, J. R., Yamada, S., Mackic, J. al. (2002). Brain clearance of Alzheimer's amyloid-β40 in the squirrel monkey: A SPECT study in a primate model of cerebral amyloid angiopathy. J. Drug Targetin., 10, 359–68
Beyreuther, K., Christen, Y. & Masters, C. L. (eds.) (2001). Neurodegenerative Disorders: Loss of Function Through Gain of Function. Berlin: Springe, 189pp
Bush, A. I., Multhaup, G., Moir, R. al. (1993). A novel zinc (II) binding site modulates the function of the βA4 amyloid protein precursor of Alzheimer's disease. J. Biol. Chem., 268, 16109–12
Bush, A. I., Pettingell, W. H., Multhaup, al. (1994). Rapid induction of Alzheimer Aβ amyloid formation by zinc. Science, 265, 1464–7
Bussière, T., Friend, P. D., Sadeghi, al. (2002). Stereologic assessment of the total cortical volume occupied by amyloid deposits and its relationship with cognitive status in aging and Alzheimer's disease. Neuroscience, 112, 75–91
Cherny, R. A., Legg, J. T., McLean, C. al. (1999). Aqueous dissolution of Alzheimer's disease Aβ amyloid deposits by biometal depletion. J. Biol. Chem., 274, 23223–8
Cherny, R. A, Barnham, K., Lynch, al. (2000). Chelation and intercalation: complementary properties in a compound for the treatment of Alzheimer's disease. J. Struct. Biol., 130, 209–16
Cummings, J. L. & Cole, G. (2002). Alzheimer disease. J. Am. Med. Assoc., 287, 2335–8
Curtain, C. C., Ali, F., Volitakis, al. (2001). Alzheimer's disease amyloid-β binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits. J. Biol. Chem., 276, 20466–73
Davies, L., Wolska, B., Hilbich, al. (1988). A4 amyloid protein deposition and the diagnosis of Alzheimer's disease: prevalence in aged brains determined by immunocytochemistry compared with conventional neuropathlogic techniques. Neurology, 38, 1688–93
DeMattos, R. B., Bales, K. R., Cummins, D. J., Dodart, J. C., Paul, S. M. & Holtzman, D. M. (2001). Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer's disease. Proc. Natl Acad. Sci., USA, 98, 8850–5
DeMattos, R. B., Bales, K R., Parsadanian, M. and Holtzman, D. M. (2002a). Plaque-associated disruption of CSF and plasma amyloid-β (Aβ) equilibrium in a mouse model of Alzheimer's disease. J. Neurochem., 81, 229–36
DeMattos, R. B., Bales, K. R., Cummins, D. J., Paul, S. M. & Holtzman, D. M. (2002b). Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer's disease. Science, 295, 2264–7
Ertekin-Taner, N., Graff-Radford, N., Younkin, L. al. (2001). Heritability of plasma amyloid β in typical late-onset Alzheimer's disease pedigrees. Genet. Epidemiol., 21, 19–30
Fishman, C. E., Cummins, D. J., Bales, K. al. (2001). Statistical aspects of quantitative image analysis of β-amyloid in the APPV717F transgenic mouse model of Alzheimer's disease. J. Neurosci. Method., 108, 145–52
Glenner, G. G. & Wong, C. W. (1984). Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun., 120, 885–90
Gold, G., Kövari, E., Corte, al. (2001). Clinical validity of Aβ-protein deposition staging in brain aging and Alzheimer disease. J. Neuropathol. Exp. Neurol., 60, 946–52
Hardy, J. & Selkoe, D. J. (2002). The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science, 297, 353–6
Hashemzadeh-Gargari, H. & Guilarte, T. R. (1999). Divalent cations modulate N-methyl-D-aspartate receptor function at the glycine site. J. Pharmacol. Exp. Ther., 290, 1356–62
Holsinger, R. M. D., McLean, C. A., Beyreuther, K., Masters, C. L. & Evin, G. (2002). Increased expression of the amyloid precursor β-secretase in Alzheimer's disease. Ann. Neurol., 51, 783–6
Helmuth, L. (2002). Long-awaited techniques spots Alzheimer's toxin. Science, 297, 752–3
Ines Dominguez, D. & DeStrooper, B. (2002). Novel therapeutic strategies provide the real test for the amyloid hypothesis of Alzheimer's disease. Trends Pharm. Sci., 23, 324–30
Jensen, M., Schröder, J., Blomberg, al. (1999). Cerebrospinal fluid Aβ42 is increased early in sporadic Alzheimer's disease and declines with disease progression. Ann. Neurol., 45, 504–11
Jobling, M. F., Huang, X., Stewart, L. al. (2001). Copper and zinc binding modulates the aggregation and neurotoxic properties of the prion peptide PrP106–126. Biochemistry, 40, 8073–84
Kang, J., Lemaire, H., Unterbeck, al. (1987). The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature, 325, 733–6
Kanski, J., Varadarajan, S., Aksenova, M. & Butterfield, D. A. (2002). Role of glycine-33 and methionine-35 in Alzheimer's amyloid β-peptide 1–42 associated oxidative stress and neurotoxicity. Biochim. Biophys. Act., 1586, 190–8
Kapaki, E., Kilidireas, K., Paraskevas, G. P., Michalopoulou, M. & Patsouris, E. (2001). Highly increased CSF tau protein and decreased β-amyloid (1–42) in sporadic CJD: a discrimination from Alzheimer's disease?J. Neurol. Neurosurg. Psychiatr., 71, 401–3
Klunk, W. E., Wang, Y., Huang, G. F., Debnath, M. L., Holt, D. P. & Mathis, C. A. (2001). Uncharged thioflavin-T derivatives bind to amyloid-beta protein with high affinity and readily enter the brain. Life Sci., 69, 1471–84
Kraszpulski, M., Soininen, H., Helisalmi, S. & Alafuzoff, I. (2001). The load and distribution of [beta]-amyloid in brain tissue of patients with Alzheimer's disease. Acta Neurol. Scand., 103, 88–92
Kung, H. F., Lee, C. W., Zhuang, Z. P., Kung, M. P., Hou, C. & Plossl, K. (2001). Novel stilbenes as probes for amyloid plaques. J. Am. Chem. Soc., 123, 12740–1
Lee, C. W., Zhuang, Z. P., Kung, M. al. (2001). Isomerization of (Z, Z) to (E, E)1-bromo-2,5-bis-(3-hydroxycarbonyl-4- hydroxy)styrylbenzene in strong base: probes for amyloid plaques in the brain. J. Med. Chem., 44, 2270–5
Lee, H. J., Zhang, Y., Zhu, C., Duff, K. & Pardridge, W. M. (2002). Imaging brain amyloid of Alzheimer disease in vivo in transgenic mice with an Aβ peptide radiopharmaceutical. J. Cereb. Blood Flow Metab., 22, 223–31
Lee, J. Y., Cole, T. B., Palmiter, R. D., Suh, S. W. & Koh, J. Y. (2002). Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice. Proc. Natl Acad. Sci., USA, 99, 7705–10
McLean, C. A., Cherny, R. A., Fraser, F. al. (1999). Soluble pool of Aβ amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann. Neurol., 46, 860–6
McLean, C. A., Beyreuther, K. & Masters, C. L. (2001). Amyloid Aβ?levels in Alzheimer's disease – a diagnostic tool and the key to understanding the natural history of Aβ?J. Alzheimer's Dis., 3, 305–12
Maruyama, M., Arai, H., Sugita, al. (2001). Cerebrospinal fluid amyloid β(1–42) levels in the mild cognitive impairment stage of Alzheimer's disease. Exp. Neurol., 172, 433–6
Masters, C. L., Simms, G., Weinman, N. A., McDonald, B. L., Multhaup, G. & Beyreuther, K. (1985). Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc. Natl Acad. Sci., USA, 82, 4245–9
Mathis, C. A., Bacskai, B. J., Kajdasz, S. al. (2002). A lipophilic thioflavin-T derivative for positron emission tomography (PET) imaging of amyloid in brain. Bioorg. Med. Chem. Lett., 12, 295–8
Mehta, P. D., Pirttila, T., Patrick, B. A., Barshatzky, M. & Mehta, S. P. (2001). Amyloid β protein 1–40 and 1–42 levels in matched cerebrospinal fluid and plasma from patients with Alzheimer disease. Neurosci. Lett., 304, 102–6
Nicoll, J. A. R., Wilkinson, D., Holmes, C., Steart, P., Markham, H. & Weller, R. O. (2003). Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report. Nat. Med., 9, 448–52
Nikaido, T., Austin, J., Rinehart, al. (1971). Studies in aging of the brain I. Isolation and preliminary characterization of Alzheimer plaques and cores. Arch. Neurol., 25, 198–211
Okamura, N., Arai, H., Maruyama, al. (2001). Serum cholesterol and cerebrospinal fluid amyloid β protein in Alzheimer's disease. J. Am. Geriat. Soc., 49, 1738–9
Opazo, C., Huang, X., Cherny, R. al. (2002). Metalloenzyme-like activity of Alzheimer's disease β-amyloid: Cu-dependent catalytic conversion of dopamine, cholesterol and biological reducing agents to neurotoxic H2O2. J. Biol. Chem., 277, 40302–8
Orgogozo, J.-M., Gilman, S., Dartigues, J.-F., et al. (2003). Subacute meningoencephalitis in a subset of patients with AD after Aβ42 immunization. Neurology, 61, 46–54
Oshima, N., Morishima-Kawashima, M., Yamaguchi, al. (2001). Accumulation of amyloid β-protein in the low-density membrane domain accurately reflects the extent of β-amyloid deposition in the brain. Am. J. Pathol., 158, 2209–18
Parvathy, S., Davies, P., Haroutunian, al. (2001). Correlation between Aβx-40-, Aβx-42-, and Aβx-43- containing amyloid plaques and cognitive decline. Arch. Neurol., 58, 2025–32
Rapoport, M., Dawson, H. N., Binder, L. I., Vitek, M. P. & Ferreira, A. (2002). Tau is essential to β-amyloid-induced neurotoxicity. Proc. Natl Acad. Sci., USA, 99, 6364–9
Revesz, T., Holton, J. L., Lashley, al. (2002). Frangione B. Sporadic and familial cerebral amyloid angiopathies. Brain. Pathol., 12, 343–57
Riemenschneider, M., Schmolke, M., Lautenschlager, al. (2002a). Association of CSF apolipoprotein E, Aβ42 and cognition in Alzheimer's disease. Neurobiol. Agin., 23, 205–11
Riemenschneider, M., Wagenpfeil, S., Diehl, al. (2002b). Tau and Aβ42 protein in CSF of patients with frontotemporal degeneration. Neurology, 58, 1622–8
Ritchie, C. W., Bush, A. I., Mackinnon, al. (2003). Metal–protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Aβ amyloid deposition and toxicity in Alzheimer's disease: a pilot Phase 2 clinical trial. Arch. Neurol., 60, 1685–91
Rösler, N., Wichart, I. & Jellinger, K. A. (2001). CSF Aβ40 and Aβ42: Natural course and clinical usefulness. J. Alzheimer's Dis., 3, 599–600
Schmidt, M. L., Schuck, T., Sheridan, al. (2001). The fluorescent Congo red derivative, (trans, trans)-1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy) styrylbenzene (BSB), labels diverse β-pleated sheet structures in postmortem human neurodegenerative disease brains. Am. J. Pathol., 159, 937–43
Schupf, N., Patel, B., Silverman, al. (2001). Elevated plasma amyloid β-peptide 1–42 and onset of dementia in adults with Down syndrome. Neurosci. Lett., 301, 199–203
Shoghi-Jadid, K., Small, G. W., Agdeppa, E. al. (2002). Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease. Am. J. Geriatr. Psychiatr., 10, 24–35
Shoji, M. & Kanai, M. (2001). Cerebrospinal fluid Aβ40 and Aβ42: natural course and clinical usefulness. J. Alzheimer's Dis., 3, 313–21
Shoji, M., Kanai, M., Matsubara, al. (2001). The levels of cerebrospinal fluid Aβ40 and Aβ42(43) are regulated age-dependently. Neurobiol. Agin., 22, 209–15
Sisodia, S. S. & St George-Hyslop, P. H. (2002). γ-Secretase, Notch, Abeta and Alzheimer's disease: where do the presenilins fit in?Nat. Rev. Neurosci. 3, 281–90
Sjögren, M., Vanderstichele, H., Ågren, al. (2001). Tau and Aβ42 in cerebrospinal fluid from healthy adults 21–93 years of age: establishment of reference values. Clin. Chem., 47, 1776–81
Sjögren, M., Davidsson, P., Wallin, al. (2002). Decreased CSF-β-amyloid 42 in Alzheimer's disease and amyotrophic lateral sclerosis may reflect mismetabolism of β-amyloid induced by disparate mechanisms. Dement. Geriatr. Cogn. Disord., 13, 112–18
Smith, M. J., Kwok, J. B. J., McLean, C. al. (2001). Variable phenotype of Alzheimer's disease with spastic paraparesis. Ann. Neurol., 49, 125–9
Tokuda, T., Tamaoka, A., Matsuno, al. (2001). Plasma levels of amyloid β proteins did not differ between subjects taking statins and those not taking statins. Ann. Neurol., 49, 546–7
Tschampa, H. J., Schulz-Schaeffer, W., Wiltfang, al. (2001). Decreased CSF amyloid β42 and normal tau levels in dementia with Lewy bodies. Neurology, 56, 576
Walsh, D. M., Klyubin, I., Fadeeva, J. al. (2002). Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature, 416, 535–9
Weiss, J. H. & Sensi, S. L. (2000). Ca2+-Zn2+permeable AMPA or kainite receptors: possible key factors in selective neurodegeneration. Trends Neurosci., 23, 365–71
Zhuang, Z. P., Kung, M. P., Hou, al. (2001a). Radioiodinated styrylbenzenes and thioflavins as probes for amyloid aggregates. J. Med. Chem., 44, 1905–14
Zhuang, Z. P., Kung, M. P., Hou, al. (2001b). IBOX(2-(4-dimethylaminophenyl)-6-iodobenzoxazole): a ligand for imaging amyloid plaques in the brain. Nucl. Med. Biol., 28, 887–94