Abstract
Alzheimer's disease is characterized neuropathologically by the progressive atrophy and death of selected neuronal populations. Prominent cytoskeletal changes are also observed, as well as the formation of neuritic plaques associated with the abnormal deposition of amyloid in the brain. The nature, pathogenesis and distribution of these changes are discussed.
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- Abraham C. R., Selkoe D. J., Potter H. Immunochemical identification of the serine protease inhibitor alpha 1-antichymotrypsin in the brain amyloid deposits of Alzheimer's disease. Cell. 1988 Feb 26;52(4):487–501. doi: 10.1016/0092-8674(88)90462-x. [DOI] [PubMed] [Google Scholar]
- Anderton B. H., Breinburg D., Downes M. J., Green P. J., Tomlinson B. E., Ulrich J., Wood J. N., Kahn J. Monoclonal antibodies show that neurofibrillary tangles and neurofilaments share antigenic determinants. Nature. 1982 Jul 1;298(5869):84–86. doi: 10.1038/298084a0. [DOI] [PubMed] [Google Scholar]
- Bancher C., Brunner C., Lassmann H., Budka H., Jellinger K., Wiche G., Seitelberger F., Grundke-Iqbal I., Iqbal K., Wisniewski H. M. Accumulation of abnormally phosphorylated tau precedes the formation of neurofibrillary tangles in Alzheimer's disease. Brain Res. 1989 Jan 16;477(1-2):90–99. doi: 10.1016/0006-8993(89)91396-6. [DOI] [PubMed] [Google Scholar]
- Bergeron C., Ranalli P. J., Miceli P. N. Amyloid angiopathy in Alzheimer's disease. Can J Neurol Sci. 1987 Nov;14(4):564–569. [PubMed] [Google Scholar]
- Binder L. I., Frankfurter A., Rebhun L. I. The distribution of tau in the mammalian central nervous system. J Cell Biol. 1985 Oct;101(4):1371–1378. doi: 10.1083/jcb.101.4.1371. [DOI] [PMC free article] [PubMed] [Google Scholar]
- D'Amato R. J., Zweig R. M., Whitehouse P. J., Wenk G. L., Singer H. S., Mayeux R., Price D. L., Snyder S. H. Aminergic systems in Alzheimer's disease and Parkinson's disease. Ann Neurol. 1987 Aug;22(2):229–236. doi: 10.1002/ana.410220207. [DOI] [PubMed] [Google Scholar]
- Delabar J. M., Goldgaber D., Lamour Y., Nicole A., Huret J. L., de Grouchy J., Brown P., Gajdusek D. C., Sinet P. M. Beta amyloid gene duplication in Alzheimer's disease and karyotypically normal Down syndrome. Science. 1987 Mar 13;235(4794):1390–1392. doi: 10.1126/science.2950593. [DOI] [PubMed] [Google Scholar]
- Dickson D. W., Farlo J., Davies P., Crystal H., Fuld P., Yen S. H. Alzheimer's disease. A double-labeling immunohistochemical study of senile plaques. Am J Pathol. 1988 Jul;132(1):86–101. [PMC free article] [PubMed] [Google Scholar]
- Doebler J. A., Markesbery W. R., Anthony A., Rhoads R. E. Neuronal RNA in relation to neuronal loss and neurofibrillary pathology in the hippocampus in Alzheimer's disease. J Neuropathol Exp Neurol. 1987 Jan;46(1):28–39. doi: 10.1097/00005072-198701000-00003. [DOI] [PubMed] [Google Scholar]
- Dyrks T., Weidemann A., Multhaup G., Salbaum J. M., Lemaire H. G., Kang J., Müller-Hill B., Masters C. L., Beyreuther K. Identification, transmembrane orientation and biogenesis of the amyloid A4 precursor of Alzheimer's disease. EMBO J. 1988 Apr;7(4):949–957. doi: 10.1002/j.1460-2075.1988.tb02900.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Giaccone G., Tagliavini F., Linoli G., Bouras C., Frigerio L., Frangione B., Bugiani O. Down patients: extracellular preamyloid deposits precede neuritic degeneration and senile plaques. Neurosci Lett. 1989 Feb 13;97(1-2):232–238. doi: 10.1016/0304-3940(89)90169-9. [DOI] [PubMed] [Google Scholar]
- Glenner G. G., Henry J. H., Fujihara S. Congophilic angiopathy in the pathogenesis of Alzheimer's degeneration. Ann Pathol. 1981;1(2):120–129. [PubMed] [Google Scholar]
- Glenner G. G., Wong C. W. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun. 1984 May 16;120(3):885–890. doi: 10.1016/s0006-291x(84)80190-4. [DOI] [PubMed] [Google Scholar]
- Goldgaber D., Lerman M. I., McBride O. W., Saffiotti U., Gajdusek D. C. Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease. Science. 1987 Feb 20;235(4791):877–880. doi: 10.1126/science.3810169. [DOI] [PubMed] [Google Scholar]
- Goldman J. E., Yen S. H. Cytoskeletal protein abnormalities in neurodegenerative diseases. Ann Neurol. 1986 Mar;19(3):209–223. doi: 10.1002/ana.410190302. [DOI] [PubMed] [Google Scholar]
- Grundke-Iqbal I., Iqbal K., Tung Y. C., Quinlan M., Wisniewski H. M., Binder L. I. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A. 1986 Jul;83(13):4913–4917. doi: 10.1073/pnas.83.13.4913. [DOI] [PMC free article] [PubMed] [Google Scholar]
- HIRANO A., ZIMMERMAN H. M. Alzheimer's neurofibrillary changes. A topographic study. Arch Neurol. 1962 Sep;7:227–242. doi: 10.1001/archneur.1962.04210030065009. [DOI] [PubMed] [Google Scholar]
- Hirano A., Dembitzer H. M., Kurland L. T., Zimmerman H. M. The fine structure of some intraganglionic alterations. Neurofibrillary tangles, granulovacuolar bodies and "rod-like" structures as seen in Guam amyotrophic lateral sclerosis and parkinsonism-dementia complex. J Neuropathol Exp Neurol. 1968 Apr;27(2):167–182. [PubMed] [Google Scholar]
- Hirokawa N., Hisanaga S., Shiomura Y. MAP2 is a component of crossbridges between microtubules and neurofilaments in the neuronal cytoskeleton: quick-freeze, deep-etch immunoelectron microscopy and reconstitution studies. J Neurosci. 1988 Aug;8(8):2769–2779. doi: 10.1523/JNEUROSCI.08-08-02769.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hyman B. T., Van Hoesen G. W., Damasio A. R., Barnes C. L. Alzheimer's disease: cell-specific pathology isolates the hippocampal formation. Science. 1984 Sep 14;225(4667):1168–1170. doi: 10.1126/science.6474172. [DOI] [PubMed] [Google Scholar]
- KIDD M. ALZHEIMER'S DISEASE--AN ELECTRON MICROSCOPICAL STUDY. Brain. 1964 Jun;87:307–320. doi: 10.1093/brain/87.2.307. [DOI] [PubMed] [Google Scholar]
- Kang J., Lemaire H. G., Unterbeck A., Salbaum J. M., Masters C. L., Grzeschik K. H., Multhaup G., Beyreuther K., Müller-Hill B. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature. 1987 Feb 19;325(6106):733–736. doi: 10.1038/325733a0. [DOI] [PubMed] [Google Scholar]
- Katzman R., Terry R., DeTeresa R., Brown T., Davies P., Fuld P., Renbing X., Peck A. Clinical, pathological, and neurochemical changes in dementia: a subgroup with preserved mental status and numerous neocortical plaques. Ann Neurol. 1988 Feb;23(2):138–144. doi: 10.1002/ana.410230206. [DOI] [PubMed] [Google Scholar]
- Kitaguchi N., Takahashi Y., Tokushima Y., Shiojiri S., Ito H. Novel precursor of Alzheimer's disease amyloid protein shows protease inhibitory activity. Nature. 1988 Feb 11;331(6156):530–532. doi: 10.1038/331530a0. [DOI] [PubMed] [Google Scholar]
- Kosik K. S., Duffy L. K., Dowling M. M., Abraham C., McCluskey A., Selkoe D. J. Microtubule-associated protein 2: monoclonal antibodies demonstrate the selective incorporation of certain epitopes into Alzheimer neurofibrillary tangles. Proc Natl Acad Sci U S A. 1984 Dec;81(24):7941–7945. doi: 10.1073/pnas.81.24.7941. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kowall N. W., Beal M. F. Cortical somatostatin, neuropeptide Y, and NADPH diaphorase neurons: normal anatomy and alterations in Alzheimer's disease. Ann Neurol. 1988 Feb;23(2):105–114. doi: 10.1002/ana.410230202. [DOI] [PubMed] [Google Scholar]
- Ksiezak-Reding H., Davies P., Yen S. H. Alz 50, a monoclonal antibody to Alzheimer's disease antigen, cross-reacts with tau proteins from bovine and normal human brain. J Biol Chem. 1988 Jun 15;263(17):7943–7947. [PubMed] [Google Scholar]
- Lee V. M., Otvos L., Jr, Schmidt M. L., Trojanowski J. Q. Alzheimer disease tangles share immunological similarities with multiphosphorylation repeats in the two large neurofilament proteins. Proc Natl Acad Sci U S A. 1988 Oct;85(19):7384–7388. doi: 10.1073/pnas.85.19.7384. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Manetto V., Abdul-Karim F. W., Perry G., Tabaton M., Autilio-Gambetti L., Gambetti P. Selective presence of ubiquitin in intracellular inclusions. Am J Pathol. 1989 Mar;134(3):505–513. [PMC free article] [PubMed] [Google Scholar]
- Mann D. M., Lincoln J., Yates P. O., Stamp J. E., Toper S. Changes in the monoamine containing neurones of the human CNS in senile dementia. Br J Psychiatry. 1980 Jun;136:533–541. doi: 10.1192/bjp.136.6.533. [DOI] [PubMed] [Google Scholar]
- Mann D. M., Yates P. O., Marcyniuk B. Some morphometric observations on the cerebral cortex and hippocampus in presenile Alzheimer's disease, senile dementia of Alzheimer type and Down's syndrome in middle age. J Neurol Sci. 1985 Jul;69(3):139–159. doi: 10.1016/0022-510x(85)90129-7. [DOI] [PubMed] [Google Scholar]
- Miller C. C., Brion J. P., Calvert R., Chin T. K., Eagles P. A., Downes M. J., Flament-Durand J., Haugh M., Kahn J., Probst A. Alzheimer's paired helical filaments share epitopes with neurofilament side arms. EMBO J. 1986 Feb;5(2):269–276. doi: 10.1002/j.1460-2075.1986.tb04209.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mobley W. C., Neve R. L., Prusiner S. B., McKinley M. P. Nerve growth factor increases mRNA levels for the prion protein and the beta-amyloid protein precursor in developing hamster brain. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9811–9815. doi: 10.1073/pnas.85.24.9811. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Monard D. Cell-derived proteases and protease inhibitors as regulators of neurite outgrowth. Trends Neurosci. 1988 Dec;11(12):541–544. doi: 10.1016/0166-2236(88)90182-8. [DOI] [PubMed] [Google Scholar]
- Mori H., Kondo J., Ihara Y. Ubiquitin is a component of paired helical filaments in Alzheimer's disease. Science. 1987 Mar 27;235(4796):1641–1644. doi: 10.1126/science.3029875. [DOI] [PubMed] [Google Scholar]
- Neary D., Snowden J. S., Mann D. M., Bowen D. M., Sims N. R., Northen B., Yates P. O., Davison A. N. Alzheimer's disease: a correlative study. J Neurol Neurosurg Psychiatry. 1986 Mar;49(3):229–237. doi: 10.1136/jnnp.49.3.229. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Neve R. L., Finch E. A., Dawes L. R. Expression of the Alzheimer amyloid precursor gene transcripts in the human brain. Neuron. 1988 Oct;1(8):669–677. doi: 10.1016/0896-6273(88)90166-3. [DOI] [PubMed] [Google Scholar]
- Nukina N., Kosik K. S., Selkoe D. J. The monoclonal antibody, Alz 50, recognizes tau proteins in Alzheimer's disease brain. Neurosci Lett. 1988 May 3;87(3):240–246. doi: 10.1016/0304-3940(88)90455-7. [DOI] [PubMed] [Google Scholar]
- Palmert M. R., Golde T. E., Cohen M. L., Kovacs D. M., Tanzi R. E., Gusella J. F., Usiak M. F., Younkin L. H., Younkin S. G. Amyloid protein precursor messenger RNAs: differential expression in Alzheimer's disease. Science. 1988 Aug 26;241(4869):1080–1084. doi: 10.1126/science.2457949. [DOI] [PubMed] [Google Scholar]
- Pearson R. C., Esiri M. M., Hiorns R. W., Wilcock G. K., Powell T. P. Anatomical correlates of the distribution of the pathological changes in the neocortex in Alzheimer disease. Proc Natl Acad Sci U S A. 1985 Jul;82(13):4531–4534. doi: 10.1073/pnas.82.13.4531. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Perry G., Lipphardt S., Mulvihill P., Kancherla M., Mijares M., Gambetti P., Sharma S., Maggiora L., Cornette J., Lobl T. Amyloid precursor protein in senile plaques of Alzheimer disease. Lancet. 1988 Sep 24;2(8613):746–746. doi: 10.1016/s0140-6736(88)90219-x. [DOI] [PubMed] [Google Scholar]
- Podlisny M. B., Lee G., Selkoe D. J. Gene dosage of the amyloid beta precursor protein in Alzheimer's disease. Science. 1987 Oct 30;238(4827):669–671. doi: 10.1126/science.2960019. [DOI] [PubMed] [Google Scholar]
- Ponte P., Gonzalez-DeWhitt P., Schilling J., Miller J., Hsu D., Greenberg B., Davis K., Wallace W., Lieberburg I., Fuller F. A new A4 amyloid mRNA contains a domain homologous to serine proteinase inhibitors. Nature. 1988 Feb 11;331(6156):525–527. doi: 10.1038/331525a0. [DOI] [PubMed] [Google Scholar]
- Probst A., Basler V., Bron B., Ulrich J. Neuritic plaques in senile dementia of Alzheimer type: a Golgi analysis in the hippocampal region. Brain Res. 1983 Jun 6;268(2):249–254. doi: 10.1016/0006-8993(83)90490-0. [DOI] [PubMed] [Google Scholar]
- Probst A., Brunnschweiler H., Lautenschlager C., Ulrich J. A special type of senile plaque, possibly an initial stage. Acta Neuropathol. 1987;74(2):133–141. doi: 10.1007/BF00692843. [DOI] [PubMed] [Google Scholar]
- Scheibel A. B., Tomiyasu U. Dendritic sprouting in Alzheimer's presenile dementia. Exp Neurol. 1978 May 15;60(1):1–8. doi: 10.1016/0014-4886(78)90164-4. [DOI] [PubMed] [Google Scholar]
- Schmechel D. E., Goldgaber D., Burkhart D. S., Gilbert J. R., Gajdusek D. C., Roses A. D. Cellular localization of messenger RNA encoding amyloid-beta-protein in normal tissue and in Alzheimer disease. Alzheimer Dis Assoc Disord. 1988;2(2):96–111. doi: 10.1097/00002093-198802020-00002. [DOI] [PubMed] [Google Scholar]
- Selkoe D. J., Ihara Y., Salazar F. J. Alzheimer's disease: insolubility of partially purified paired helical filaments in sodium dodecyl sulfate and urea. Science. 1982 Mar 5;215(4537):1243–1245. doi: 10.1126/science.6120571. [DOI] [PubMed] [Google Scholar]
- Selkoe D. J., Podlisny M. B., Joachim C. L., Vickers E. A., Lee G., Fritz L. C., Oltersdorf T. Beta-amyloid precursor protein of Alzheimer disease occurs as 110- to 135-kilodalton membrane-associated proteins in neural and nonneural tissues. Proc Natl Acad Sci U S A. 1988 Oct;85(19):7341–7345. doi: 10.1073/pnas.85.19.7341. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shivers B. D., Hilbich C., Multhaup G., Salbaum M., Beyreuther K., Seeburg P. H. Alzheimer's disease amyloidogenic glycoprotein: expression pattern in rat brain suggests a role in cell contact. EMBO J. 1988 May;7(5):1365–1370. doi: 10.1002/j.1460-2075.1988.tb02952.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Snow A. D., Mar H., Nochlin D., Kimata K., Kato M., Suzuki S., Hassell J., Wight T. N. The presence of heparan sulfate proteoglycans in the neuritic plaques and congophilic angiopathy in Alzheimer's disease. Am J Pathol. 1988 Dec;133(3):456–463. [PMC free article] [PubMed] [Google Scholar]
- St George-Hyslop P. H., Tanzi R. E., Polinsky R. J., Neve R. L., Pollen D., Drachman D., Growdon J., Cupples L. A., Nee L., Myers R. H. Absence of duplication of chromosome 21 genes in familial and sporadic Alzheimer's disease. Science. 1987 Oct 30;238(4827):664–666. doi: 10.1126/science.2890206. [DOI] [PubMed] [Google Scholar]
- Sternberger N. H., Sternberger L. A., Ulrich J. Aberrant neurofilament phosphorylation in Alzheimer disease. Proc Natl Acad Sci U S A. 1985 Jun;82(12):4274–4276. doi: 10.1073/pnas.82.12.4274. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Struble R. G., Powers R. E., Casanova M. F., Kitt C. A., Brown E. C., Price D. L. Neuropeptidergic systems in plaques of Alzheimer's disease. J Neuropathol Exp Neurol. 1987 Sep;46(5):567–584. doi: 10.1097/00005072-198709000-00006. [DOI] [PubMed] [Google Scholar]
- Tanzi R. E., Bird E. D., Latt S. A., Neve R. L. The amyloid beta protein gene is not duplicated in brains from patients with Alzheimer's disease. Science. 1987 Oct 30;238(4827):666–669. doi: 10.1126/science.2890207. [DOI] [PubMed] [Google Scholar]
- Tanzi R. E., Gusella J. F., Watkins P. C., Bruns G. A., St George-Hyslop P., Van Keuren M. L., Patterson D., Pagan S., Kurnit D. M., Neve R. L. Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science. 1987 Feb 20;235(4791):880–884. doi: 10.1126/science.2949367. [DOI] [PubMed] [Google Scholar]
- Tanzi R. E., McClatchey A. I., Lamperti E. D., Villa-Komaroff L., Gusella J. F., Neve R. L. Protease inhibitor domain encoded by an amyloid protein precursor mRNA associated with Alzheimer's disease. Nature. 1988 Feb 11;331(6156):528–530. doi: 10.1038/331528a0. [DOI] [PubMed] [Google Scholar]
- Tanzi R. E., St George-Hyslop P. H., Haines J. L., Polinsky R. J., Nee L., Foncin J. F., Neve R. L., McClatchey A. I., Conneally P. M., Gusella J. F. The genetic defect in familial Alzheimer's disease is not tightly linked to the amyloid beta-protein gene. Nature. 1987 Sep 10;329(6135):156–157. doi: 10.1038/329156a0. [DOI] [PubMed] [Google Scholar]
- Tate-Ostroff B., Majocha R. E., Marotta C. A. Identification of cellular and extracellular sites of amyloid precursor protein extracytoplasmic domain in normal and Alzheimer disease brains. Proc Natl Acad Sci U S A. 1989 Jan;86(2):745–749. doi: 10.1073/pnas.86.2.745. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Terry R. D., Hansen L. A., DeTeresa R., Davies P., Tobias H., Katzman R. Senile dementia of the Alzheimer type without neocortical neurofibrillary tangles. J Neuropathol Exp Neurol. 1987 May;46(3):262–268. doi: 10.1097/00005072-198705000-00003. [DOI] [PubMed] [Google Scholar]
- Ulrich J. Alzheimer changes in nondemented patients younger than sixty-five: possible early stages of Alzheimer's disease and senile dementia of Alzheimer type. Ann Neurol. 1985 Mar;17(3):273–277. doi: 10.1002/ana.410170309. [DOI] [PubMed] [Google Scholar]
- Van Broeckhoven C., Genthe A. M., Vandenberghe A., Horsthemke B., Backhovens H., Raeymaekers P., Van Hul W., Wehnert A., Gheuens J., Cras P. Failure of familial Alzheimer's disease to segregate with the A4-amyloid gene in several European families. Nature. 1987 Sep 10;329(6135):153–155. doi: 10.1038/329153a0. [DOI] [PubMed] [Google Scholar]
- Whitehouse P. J., Price D. L., Struble R. G., Clark A. W., Coyle J. T., Delon M. R. Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain. Science. 1982 Mar 5;215(4537):1237–1239. doi: 10.1126/science.7058341. [DOI] [PubMed] [Google Scholar]
- Whitson J. S., Selkoe D. J., Cotman C. W. Amyloid beta protein enhances the survival of hippocampal neurons in vitro. Science. 1989 Mar 17;243(4897):1488–1490. doi: 10.1126/science.2928783. [DOI] [PubMed] [Google Scholar]
- Wischik C. M., Novak M., Edwards P. C., Klug A., Tichelaar W., Crowther R. A. Structural characterization of the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci U S A. 1988 Jul;85(13):4884–4888. doi: 10.1073/pnas.85.13.4884. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wolozin B. L., Pruchnicki A., Dickson D. W., Davies P. A neuronal antigen in the brains of Alzheimer patients. Science. 1986 May 2;232(4750):648–650. doi: 10.1126/science.3083509. [DOI] [PubMed] [Google Scholar]
- Yagishita S., Itoh Y., Nan W., Amano N. Reappraisal of the fine structure of Alzheimer's neurofibrillary tangles. Acta Neuropathol. 1981;54(3):239–246. doi: 10.1007/BF00687747. [DOI] [PubMed] [Google Scholar]
- Yen S. H., Dickson D. W., Crowe A., Butler M., Shelanski M. L. Alzheimer's neurofibrillary tangles contain unique epitopes and epitopes in common with the heat-stable microtubule associated proteins tau and MAP2. Am J Pathol. 1987 Jan;126(1):81–91. [PMC free article] [PubMed] [Google Scholar]





