Cajal's Contributions to the Study of Alzheimer's

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Journal of Alzheimer’s Disease 12 (2007) 161–174 IOS Press

Cajal’s Contributions to the Study of Alzheimer’s Disease Virginia Garc´ıa-Mar´ın1,∗ , Pablo Garc´ıa-López1 and Miguel Freire Museum Ramo´ n y Cajal, Instituto Cajal, CSIC, Avda. Doctor Arce, 37; Madrid – 28002, Spain

Abstract. Last year 2006, we commemorated two important events in the history of Neuroscience. One hundred years ago, on November 3, Alois Alzheimer (1864–1915) presented the first case of a patient with symptoms of a disease that later would be called Alzheimer’s disease. One month later, on December 10, Santiago Ramón y Cajal (1852–1934) and Camilo Golgi (1843–1926) received the Nobel Prize “in recognition of their work on the structure of the Nervous System”. These facts seem not to be related, but working in the Museum Cajal we found 37 histological preparations of material from patients suffering from Alzheimer’s disease, revealing that Cajal also studied this disease. This paper deals with Cajal’s contribution to the study of Alzheimer’s disease and it is fully illustrated by original pictures of Cajal’s slides preserved in the Cajal Museum, Madrid. Keywords: Cajal, Alzheimer’s disease, senile plaques, neurofibrillary tangles

INTRODUCTION Ramón y Cajal is broadly known by his studies of the anatomy, functional organization and development of the nervous system. However, his observations and theories on pathology of the nervous systems are little known, with the exception of his experimental studies about degeneration and regeneration of the nervous system [113]. Cajal made important contributions to pathological anatomy including his studies on cancer [82], Alzheimer’s disease (AD), neurosyphilis, Korsakoff’s syndrome, and rabies. AD is one of the most important neurological disorders. Since it was discovered by Alzheimer in 1906, much research has been done in order to clarify the mechanism that underlies the disease. Cajal also paid attention to this disorder and following his own research about degeneration and regeneration of the nervous system gave some ideas about the degenerative and regenerative processes that occur in AD. Our aim is to study the original histological preparations conserved in the Museum Cajal from patients suf1 These

authors contributed equally to this work. ∗ Address for correspondence. Tel.: +34 91 585 47 43; Fax: +34 91 585 47 53; E-mail: [email protected].

fering from AD. We will show original pictures of the main pathological hallmarks of AD taken from these slides, and review some of Cajal’s ideas about AD from a historical and present-day perspective. Cajal’s main contributions to AD are summarized in his Spanish books Degeneraci o´ n y Regeneraci o´ n del sistema nervioso2 [113] and Manual General de Anatomia patológica y bacteriolog´ıa 3 [117].

CAJAL’S HISTOLOGICAL PREPARATIONS In the Museum Cajal, 4,529 histological preparations of Cajal are conserved, 690 are related to pathology: cancer (92 slides), degeneration and regeneration of the nervous system (391), AD (37), neurosyphilis (135), Korsakoff syndrome (17) and rage (18). Among Cajal’s histological preparations of AD (Fig. 1), we have found different histological methods. Table 1 summarizes the different components of each method and their main staining targets. Cajal used to write on the labels of his 2 This

book has been translated into English in 1928 (translation by May) [114] and 1991 (translation by translation by May, with introduction and additional translation by DeFelipe and Jones) [115]. 3 Not English version of this book.

ISSN 1387-2877/07/$17.00  2007 – IOS Press and the authors. All rights reserved

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Box 1 Cajal proposed his neurotropic hypothesis, firstly named chymiotactic hypothesis in 1893 [102]. He proposed the existence of neurotropic substances for explaining the guidance of axons to their targets during development. Cajal also admitted the secretion of neurotropic substances by intermediate targets. For instance, he explained the attraction of commissural axons to the ventral part of the epithelial barrel during the development of the spinal cord, as later was demonstrated discovering the secretion of netrins by the floor plate [64,126]. “It would be explained by the production of inducting substances of great force at the level of the ventral half of the epithelial barrel” [104]. Furthermore Cajal admitted the possibility of negative neurotropism [102,116] although in some parts of his work he negated this possibility [113]. However this Cajal’s concept of neurotropic substance evolved to a concept of neurotrophic agents especially under pathological conditions, in which the substances secreted by the Schwann cells would create the trophic ambient necessary for the growing of the axonal sprouts. “These substances have not only an orientating function, but they are also trophic in character, since the sprouts that have arrived at the peripheral stump are robust, show a great capacity for ramification and grow straight to their target without vacillations, as though they were following an irresistible attraction” [113]. Nowadays, this double concept of Cajal is still valuable for developing and regenerating nervous system, i) the growth and maturation of cells, under the influence of neurotrophic substances, and ii) the direction of neuronal processes, depending on neurotropic substances, mediated by guidance cues that can act attracting or repelling dendrites or axons. In this last group of neurotropic substances are also included surface-bound adhesive molecules. As examples of neurotrophic substances which allowed the growth and maturation are found neurotrophins such as; NGF [72,73], BDNF [13,29], NT-3, and NT4/5 [15,78] and their receptors (the trk receptor tyrosine kinases and the p75 neurotrophin receptors) [63,95]. On the other hand, neurotropic substances can act on axons such as: Netrins [127-64] /DCC-Unc [57,61], semaphorins [69,77] /plexinsNeuropilin [25,44,56,143], and Slits [22,65] /Robo [66,149]; on dendrites, for instance LNotch [14,127], Beta-catenin [148], Numb [121,127], Rho family of GTPases [52,76]; and on synapses for example: CAMs [16,135], integrins [93,36], cadherins [125,26], neurexinneuroligin [124,130] and syndecan 2 [38,58].

More studies focused on nerve growth factors are necessary to understand the mechanism of neurodegenerative disorders and their treatment. In addition growth factors constitute a therapeutic approach for the treatment of the disease. Neurofibrillary pathology Neurofibrillary tangles were described by Alzheimer [3]. At Cajal’s time, scientists called them “Alzheimer lesions” as we can see in Cajal’s preparations (Fig. 1) and writings [117]. Alzheimer wrote “Specimens which were prepared according to Bielschowsky’s silver method show very striking changes of the neurofibrils. Inside of a cell which appears to be quite normal, one or several fibrils can be distinguished by their unique thickness and capacity for impregnation. Further examination shows many fibrils located next to each other which have been changed in the same way. Next, combined in thick bundles, they appear one by one at the surface of the cell. Finally, the nucleus and the cell itself disintegrate and only a tangle of fibrils indicates the place where a neuron was previously located” (Fig. 5J) [3,53,133]. Interestingly, Cajal also observed neurofibrillar alterations in physiological and pathological conditions such as hibernation, rage, or after a wound in the nervous system (Box 2). The different morphological variants of tangles found are in part due to the nature of the neurons in which they were formed. Flame-shaped NFT are characteristic of pyramidal neurons, and globose NFT are

found in large non-pyramidal neurons [34]. The flameshaped NFT sometimes have a great apical process that follows the direction of the apical dendrite (Fig. 5D–F). In addition, we have found other lesions related to neurofibrillary degeneration, neuropil threads and dystrophic neurites. Neuropil threads are short and tortuous argyrophilic neurites dispersed in the neuropil that are immunoreactive for tau [21]. Most neuropil threads are probably derived from dendritic processes [20], but up to 10% have been identified as myelinated axons with electron microscopy [94,100]. Dystrophic neurites appear surrounding the corona of neuritic senile plaques (Fig. 4). These dystrophic neurites could be the crown of nervous buds which Cajal refers to in 1918. Cajal specially proposed that these dystrophic neurites were axonal sprouts with terminal clubs directed to the plaque because the influence of some neurotropic substances. Interestingly these axonal sprouts were firstly seen by Cajal in regenerating axonal process after the section of the sciatic nerve (Fig. 7) [109,110] and also confirmed by Perroncito [98]. In addition to the axonal sprouting [45,46,59,84,85],dendritic sprouting [6–9,41,60,71,89,96,123] have been confirmed in AD. This process of dendritic regeneration is mediated by structures that resemble dendritic growth cones Interestingly dendritic neoformation was observed by Cajal [110] in the sensitive ganglion of old humans and dogs and in the hippocampus of old dogs by Rodriguez Lafora [71], disciple of Cajal and Alzheimer. The regeneration studies of Cajal influenced the initial studies of AD. Fischer proposed that the senile


modify its own structural organization and functionings as an adaptative response to functional demands which is impaired in AD” [5]. Coming back to Cajal and the loss of plasticity in the adult brain he stated: “Such plasticity of the cellular processes probably varies at different ages: greater in the young man, diminished in the adult and almost completely disappeared in the aged” [31,103].

GLIAL ALTERATION Cajal observed that astrocytes in the senile plaques showed hypertrophy in their bodies and appendages, and that some of these processes ended in balls [117]. This hypertrophy of astrocytes is clear in his histological preparations (Fig. 6), some of them are extremely big and show a great quantity of gliofilaments as was firstly noticed by Alzheimer in his famous report of Auguste, D. [3] “The glia have developed numerous fibers and other glial cells have large lipid droplets”. Astrocytes acquire a fibrous character like the astrocytes in white matter. The processes of the astrocytes surround the senile plaques. Mature senile plaques are not only wrapped by astrocytic processes, but they also penetrate the plaque core [79,92]. Astrocytes secrete growth factors such as nerve growth factor (NGF), basic fibroblast growth factor (BFGF), etc. which are essential for survival and terminal remodeling of the surviving neurons because they act as a trophic stimulus inducing axonal growth and sprouting [74,137,140,142]. Furthermore, in AD there is an alteration in microglial cells, with hypertrophy and changes in their morphology towards round-shaped macrophage-like cells. Microglial cells were found surrounding senile plaques (Fig. 6B–C, E). Activated microglia are most evident in dense cored plaques [10,141]. These microglia have a very important role in the process of inflammation as Fischer point out in 1910. He thought that “the foreign substance” provoked the neuroregenerative response by inflammation, although he could not find morphological signs of an inflammation process around the plaques. In the eighties of the last century using monoclonals antibodies directed against cells of the monocyte-macrophage cell lineage, senile plaques were shown to be associated with clusters of activated microglia [88,120,122]. The neuroinflammatory response includes a local upregulation of acutephase proteins, complement, cytokines and other inflammatory mediators [2]. However the diffuse plaques are no associated with activated microglia

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CONCLUSIONS Cajal described his findings about AD more than 10 years later than Alzheimer published his first article in 1907. However, it is still useful to review his slides and writings in order to compare them with the actual knowledge about the disease and also to point out some of the ideas proposed by Cajal. The staining methods used by Cajal, such as reduced silver nitrate, sublimated gold chloride, ammoniacal silver oxide, and the Bielschowsky method, are very useful to observe the many alterations in AD. Ammoniacal silver oxide and the Bielschowsky methods give a general idea of the brain alterations because they stain senile plaques, neurofibrillar lesions, reactive microglia, and active astrocytes. The reduced silver nitrate method is very useful to observe the evolution of the senile plaques, and finally, the sublimated gold chloride method allows a specific study of reactive astrocytes. These classic staining methods can still be useful in the research of this pathology, because today we can re-interpret them taking into account the knowledge acquired using specific antibodies. Furthermore, with the use of specific antibodies only we may loose and overlook other components of the senile plaques and neurofibrillary tangles already shown by the classical staining methods. The original works of the pioneers and Cajal in the study of AD still propose hypotheses and questions that we have to corroborate and/or to answer to be able to advance the knowledge of AD. For instance, Cajal proposed in the evolution of senile plaques a degeneration of neurites in the surrounding area. Nowadays with modern technique it has been observed disruptions in neurites trajectories and reductions in dendritic spine density in the regions near the plaques have been observed. The dystrophic neurites (both axonal and dendritic origin) present swellings on their structure that was observed by Cajal with his silver nitrate method as we can see in his drawing. Moreover, Cajal suggested that axonal sprouts could be attracted towards the region of the plaque, under the influence of some special neurotropic substance. Future research should clarify these issues in order to advance in the knowledge of AD.

ACKNOWLEGDEMENTS We acknowledge Santiago Ram o´ n y Cajal Junquera for his help studying the histological preparations and

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Isidro Ferrer for his useful advices. Original drawings from the Museum Cajal are reproduced with permission from the Inheritors of Santiago Ram o´ n y Cajal . The authors are supported by the Spanish Ministry of Health (ISCIII, PI04/0594) and the Areces Foundation.

[13]

[14]

[15]

References [1]

N. Achúcarro and M. Gayarre, Contribución al estudio de la neuroglia en la corteza de la demencia senil y su participación en la alteración celular de Alzheimer, Trab Lab Inv Biol 12 (1914), 67–83. [2] H. Akiyama, S. Barger, S. Barnum, B. Bradt, J. Bauer, C.M. Cole, N.R. Cooper, P. Eikelenboom, M. Emmerling, B.L. Fiebich, C.E. Finch, S. Frautschy, W.S. Griffin, H. Hampel, M. Hull, G. Landreth, L. Lue, R. Mrak, I.R. Mackenzie, P.L. McGeer, M.K. O’Banion, J. Pachter, G. Pasinetti, C. Plata-Salaman, J. Rogers, R. Rydel, W. Streit, R. Strohmeyer, I. Tooyoma, F.L. Van Muiswinkel, R. Veerhuis, D. Walker, S. Webster, B. Wegrzyniak, G. Wenk and T. Wyss-Coray, Inflammation and Alzheimer’s disease, Neurobiol Aging 21 (2000), 383–421. ¨ [3] A. Alzheimer, Uber eine eigenartige Erkrankung der Hirnrinde, Allg Zeitschr Psychiatr 64 (1907), 146–148. [4] T. Arendt, J.Stieler, A.M. Strijkstra, R. Hut, J.Rüdiger, E.A. Van der Zee, T. Harkany, M. Holzer and W. Härtig, Reversible paired helical filament-like phosphorylation of Tau is an adaptive process associated with neuronal plasticity in hibernating animals, J Neuroscience 23 (2003), 6972–6981. [5] T. Arend, Alzheimer’s disease as a disorder of mechanism underlying structural brain self-organization, Neuroscience 102 (2001), 723–765. [6] T. Arendt, M.K. Brucker, V. Bigl and L. Marcova, Dendritic reorganisation in the basal forebrain under degenerative conditions and its defects in Alzheimer’s disease. III. The basal forebrain compared with other subcortical areas, J Comp Neurol 351 (1995), 189–222. [7] T. Arendt and M.K. Bruckner, Perisomatic sprouts immunoreactive for nerve growth factor receptor and neurofibrillary degeneration affect different neuronal populations in the basal nucleus in patients with Alzheimer’s disease, Neurosci Lett 148 (1992), 63–66. [8] T. Arendt, M.K. Bruckner and V. Bigl, Maintenance of neuronal plasticity in the reticular core and changes in trophic activity in Alzheimer’s disease, Am N Y Acad Sci 640 (1991), 210–214. [9] T. Arendt, H.G. Zyegintseva and T.A. Leontovich, Dendritic changes in the basal nucleus of Meynert and in the diagonal band nucleus in Alzheimer’s disease – a quantitative Golgi investigation, Neuroscience 19 (1986), 1265–1278. [10] Y.M. Arendt, C. Duyckaerts, J.M. Rozemuller, P. Eikelenboom and J.-J. Hauw, Microglia, amyloid and dementia in Alzheimer disease. A correlative study, Neurobiol Aging 21 (2000), 39–47. [11] R.A. Armstrong, β-Amyloid plaques: stages in life history or independt origin? Demt Geriatr Cogn Disord 9 (1998), 227–238. [12] M. Barcikowska, H.M. Wisniewski, C. Bancher and I. Grundke-Iqbal, About the presence of paired helical filaments in dystrophic neurites participating in the plaque formation, Acta Neuropathol (Berl) 78 (1989), 225–231.

[16]

[17] [18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26] [27]

[28]

[29]

Y.A. Barde, A.M. Davies, J.E. Johnson, R.M. Lindsay and H. Thoenen, Brain derived neurotrophic factor, Prog Brain Res 71 (1987), 185–189. O. Berezovska, P. McLean, R. Knowles, M. Frosh, F.M. Lu, S.E. Lux and B.T. Hyman, Notch1 inhibits neurite outgrowth in postmitotic primary neurons, Neuroscience 93 (1999), 433–439. L.R. Berkemeier, J.W. Winslow, D.R. Kaplan, K. Nikolics, D.V. Goeddel and A. Rosenthal, Neurotrophin-5: a novel neurotrophic factor that activates trk and trkB, Neuron 7 (1991), 857–866. T. Biederer and T.C. Südhof, Cask and protein 4.1 support F-actin nucleation on neurexins, J Biol Chem 276 (2001), 47869–47876. M. Bielschowsky, Die Silberimprägnation des Neurofibrillen, Neurol Centralbl 22 (1903), 997–1006. E. Birecree, W.O. Jr Whetsell, C. Stoscheck, L.E. Jr King and L.B. Nanney, Immunoreactive epidermal growth factor receptors in neuritic plaques from patients with Alzheimer’s disease, J Neuropath Exp Neurol 47 (1988), 549–560. P. Blocq and G. Marinesco, Sur les lésions et la pathogénie del’ e´ pilepsie dite essentielle, Semaine Médicale (Paris) 12 (1982), 445–446. H. Braak and E. Braak, Neuropil threads occur in dendrites of tangle-bearing nerve cells, Neuropathol Appl Neurobiol 14 (1988), 39–44. H. Braak, E. Braak, I. Grundke-Iqbal and K. Iqbal, Occurrence of neuropil threads in the senile human brain and in Alzheimer’s disease. A third location of paired helical filaments outside of neurofilament tangles and neuritic plaques, Neurosci Lett 65 (1986), 351–355. K. Brose, K.S. Bland, K.H. Wang, D. Arnott, W. Henzel, C.S. Goodman, M. Tessier-Lavigne and T. Kidd, Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance, Cell 96 (1999), 795–806. G.J. Burbach, R. Hellweg, C.A. Haas, D. Del Turco, U. Deicke, D. Abramowski, M. Jucker, M. Staufenbiel and T. Deller, Induction of brain-derived neurotrophic factor in plaque-associated glial cells of aged APP23 transgenic mice, J Neurosci 24 (2004), 2421–2430. I. Catala, I. Ferrer, E. Galofre and I. Fabregues, Decreased numbers of dendritic spines on cortical pyramidal neurons in dementia. A quantitative Golgi study on biopsy samples, Hum Neurobiol 6 (1988), 255–259. H. Chen, A. Chedotal, Z. He, C.S. Goodman and M. TessierLavigne, Neuropilin-2 a novel member of the neuropilin family, is a high affinity receptor for the semaphorins Sema E and Sema IV but not Sema III, Neuron 19 (1997), 547–559. D.R. Colman, Neurites, synapses, and cadherins reconciled, Mol Cell Neurosci 10 (1997), 1–6 B. Connor, D. Young, P. Lawlor, W. Gal, H. Waldvogel, R.L. Faull and M. Dragunow, Trk receptor alterations in Alzheimer’s disease, Brain Res Molec Brain Res 42 (1996), 1–17. C.W. Cotman, B.J. Cummings and J.S. Whitson, The role of misdirected plasticity in plaque biogenesis and Alzheimer’s disease, in: Growth Factor and Alzheimer’s Disease, F. Hefti, Ph. Brachet, B. Will and Y. Christen, eds, Springer-Verlag, Würzburg, 1991, pp. 222–233. A.M. Davies, H. Thoenen, Y.A. Barde, The response of chick sensory neurons to brain-derived neurotrophic factor, J Neurosci 6 (1986), 1897–904.

V. Garc´ıa-Mar´ın et al. / Cajal’s Contributions to the Study of Alzheimer’s Disease [30]

[31] [32]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

[40]

[41]

[42]

[43]

[44] [45]

[46]

J.P. de Ruiter and H.B. Uylings, Morphometric and dendritic analysis of fascia dentata granule cells in human aging and senile dementia, Brain Res 402 (1987), 217–229. J. DeFelipe, Brain plasticity and mental processes: Cajal again, Nature Reviews Neuroscience 7 (2006), 811–817. V. Della Bianca, S. Dusi, E. Bianchini, I. Dal Pra and F. Rossi, β-amyloid activates O2 -forming NADPH oxidase in microglia, monocytes and neutrophils. A possible inflammatory mechanism of neuronal damage in Alzheimer’s disease, J Biol Chem 274 (1999), 15493–15499. D.W. Dickson, J. Farlo, P. Davies, H. Crystal, P. Fuld and S.H. Yen, Alzheimer’s disease: A double-labelling immonohistochemical study of senile plaques, Am J Pathol 132 (1988), 86–101. C. Duyckaerts and D.W. Dickson, Neuropathology of Alzheimer’s disease, in: Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders, D.W. Dickson, ed., ISN Neuropath Press, 2003, pp. 47–65. P. Eikelenboom, S.S. Zhan, W.A. van Gool and D. Allsop, Inflammatory mechanisms in Alzheimer’s disease, Trends Pharmacol Sci 15 (1994), 447–450. S. Einheber, L.M. Schnapp, J.L. Salzer, Z.B. Cappiello and T.A. Milner, Regional and ultrastructural distribution of the alpha 8 integrin subunit in developing and adult rat brain suggests a role in synaptic function, J Comp Neurol 370 (1996), 105–134. J. El Khoury, S.E. Hickman, C.A. Thomas, L. Cao, S.C. Silverstein and J.D. Loike, Scavenger receptor-mediated adhesion of microglia to β-amyloid fibrils, Nature 382 (1996), 716–719. I.M. Ethell and Y. Yamaguchi, Cell surface heparan sulfate proteoglycan syndecan-2 induces the maturation of dendritic spines in rat hippocampal neurons, J Cell Biol 144 (1999), 575–586. H. Fenton, P.W. Finch, J.S. Rubin, J.M. Rosenberg, W.G. Taylor, V. Kuo-leblanc, M. RodriguezWolf, A. Baird, H.M. Schipper and E.G. Stopa, Hepatocyte growth factor (HGF/SF) in Alzheimer’s disease, Brain Res 779 (1998), 262–270. I. Ferrer, C. Marin, M.J. Rey, T. Ribalta, E. Goutan, R. Blanco, E. Tolosa and E. Marti, BDNF and full-length and truncated TrkB expression in Alzheimer disease. Implications in therapeutic strategies, J Neuropathol Exp Neurol 58 (1999), 729–739. I. Ferrer, A. Aymami, A. Rovira and J.M. Grau Veciana, Growth of abnormal neurites in atypical Alzheimer’s disease. A study with the Golgi method, Acta Neuropathol (Berl) 59 (1983), 167–170. O. Fischer, Die presbyophrene Demenz, deren anatomische Grundlage und kilnische Abfrenzung, Z Ges Neurol U Psychiat 3 (1910), 371–471. O. Fischer, Miliare Nekrosen mit drusigen Wucherungen der Neurofibrillen, eine regelmässige Veränderun der Hirnrinde bei seniler Demenz, Monatschr f Psychiatr U Neurol 22 (1907), 361–372. H. Fujisawa and T. Kitsukawa, Receptors for collapsin/semaphorins, Curr Opin Neuobiol 8 (1998), 587–592. J.W. Geddes, D.T. Monaghan, C.W. Cotman, I.T. Lott, R.C. Kim and H.C. Chui, Plasticity of hippocampal circuitry in Alzheimer’s disease, Science 230 (1985), 1179–1181. H.J. Gertz, J. Cervos-Navarro and V. Ewald, The septo hippocampal pathway in patients suffering from senile dementia of Alzheimer’s type. Evidence for neuronal plasticity? Neurosci Lett 76 (1987), 228–232.

[47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

[55]

[56]

[57]

[58]

[59]

[60] [61]

[62]

[63]

[64]

171

G. Giaccone, F. Tagliavinia, G. Linoli, C. Bouras and L. Frigerio, Down’s patients: extracellular preamyloid depostis precede neuritic degeneration and senile plaques, Neurosci Lett 97 (1989), 232–238. F. Gomez-Pinilla, J.W. Lee and C.W. Cotman, Basic FGF in adult rat brain: cellular distribution andresponse to entorhinal lesion and fimbria-fornix transection, J Neurosci 12 (1992), 345–355. F. Gomez-Pinilla, B.J. Cummings and C.W. Cotman, Induction of basic fibroblast growth factor in Alzheimer’s disease pathology, NeuroReport 1 (1990), 211–214. J.L. Goodwin, E. Uemura and J.E. Cunnick, Microglial release of nitric oxide by the synergistic action of β-amyloid and IFN-γ, Brain Res 692 (1995), 207–214. G.K. Gouras, C.G. Almeida and R.H. Takahashi, Intraneuronal accumulation and origin of plaques in Alzheimer’s disease, Neurobiology Aging 26 (2005), 1235–1244. E.E. Govek, S.E. Newey and L. Van Aelst, The role of the Rho GTPases in neuronal development, Genes Dev 19 (2005), 1–49. M.B. Graeber and P. Mehraein, Reanalysis of the first case of Alzheimer’s disease, Eur Arch Psychiatry Clin Neurosci 249(Suppl 3) (1999), 10–13. K.A. Gyure, R. Durham, W F Stewart, J.E. Smialek and J.C. Troncoso, Intraneuronal Ab-Amyloid Precedes Development of Amyloid Plaques in Down Syndrome, Arch Pathol Lab Med 125 (2001), 489–492. Y. Harigaya, Y. Tomidokoro, M. Ikeda, A. Sasaki, T. Kawarabayashi, E. Matsubara, M. Kanai, T.C. Saido, S.G. Younkin and M. Shoji, Type-specific evolution of amyloid plaque and angiopathy in APPsw mice, Neurosci Lett 395 (2006), 37–41. Z. He and M. Tessier-Lavigne, Neuropilin is a receptor for the axonal chemorepellent Semaphorin III, Cell 90 (1997), 739–751. E.M. Hedgecok, J.G. Culotti and D.H. Hall, The unc-5, unc6, and unc-40 genes guide circumferential mgrations of pioneer axons and mesodermal cells on the epidermis in C. elegans, Neuron 4 (1990), 61–85. Y.P. Hsueh, F.C. Yang, V. Kharazia, S. Naisbitt, A.R. Cohen, R.J. Weinberg and M. Sheng, Direct interaction of CASK/LIN-2 and syndecan heparan sulfate proteoglycan and their overlapping distribution in neuronal synapses, J Cell Biol 142 (1998), 139–151. B.T. Hyman, L.J. Kromer and G.W. Van Hoesen, Reinnervation of the hippocampal perforant pathway zone in Alzheimer’s disease, Ann Neurol 21 (1987), 259–267. Y. Ihara, Massive somatodendritic sprouting of cortical neurons in Alzheimer’s disease, Brain Res 459 (1988), 138–144. N. Ishii, W.G. Wadsworth, B.D. Stern, J.G. Culotti and E.M. Hedgecock, UNC-6 a laminin-related protein, guides cell and pioneer axon migrations in C. elegans, Neuron 9 (1992), 873–881. L.L. Iversen, R.J. Mortishire-Smith, S.J. Pollack and M.S. Shearman, The toxicity in vitro of β-amyloid protein, Biochem J 311 (1995), 1–16. D.R. Kaplan and F.D. Miller, Neurotrophin signal transduction in the nervous system, Curr Opin Neurobiol 10 (2000), 381–391. T.E. Kennedy, T. Serafini, J.R. de la Torre and M. TessierLavigne, Netrins are difusible chemotropic factors for commisural axons in the embryonic spinal cord, Cell 78 (1994), 425–435.

172 [65]

[66]

[67]

[68]

[69]

[70]

[71]

[72]

[73]

[74]

[75]

[76] [77]

[78]

[79]

[80]

[81]

[82]

V. Garc´ıa-Mar´ın et al. / Cajal’s Contributions to the Study of Alzheimer’s Disease T. Kidd, K.S. bland and C.S. Goodman, Slit is the midline repellent for the robo receptor in Drosophila, Cell 96 (1999), 785–794. T. Kidd, K. Brose, K.J. Mitchell, R.D. Fetter, M. TessierLavigne, C.S. Goodman and G. Tear, Roundabout controls axon crossing of the CNS midline and defines a novel subfamily of evolutionarily conserved guidance receptors, Cell 92 (1998), 205–215. A. Klegeris, D.G. Walker and P.L. McGeer, Activation of macrophages by Alzheimer β amyloid peptide, Biochem Biophys Res Commun 199 (1994), 984–991. W.L. Klein, G.A. Krafft and C.E. Finch, Targeting small A β oligomers: the solution to an Alzheimer’s disease conundrum? Trends Neurosci 24 (2001), 219–224. A.L. Kolodkin, D.J. Matthes, T.P. O’Connor, N.H. Patel, A. Admon, D. Bentley and C.S. Goodman, Fasciclin IV: sequence, expresion, and function during growth cone guidance in the grasshoper embryo, Neuron 9 (1992), 831–845. K.S. Kosik, The neuritic dystrophy of Alzheimer’s Disease: degeneration or regeneration? in: Growth factors and Alzheimer’s Disease, F. Hefti, P. Brachet, B. Will and Y. Christen, eds, Springer-Verlag, Würzburg, 1991, pp. 234– 240. G. Lafora, Neoformaciones dendr´ıticas en las neuronas y alteraciones de la neuroglia en el perro senil, Trab Lab Inv Biol 12 (1914), 39–53. R. Levi-Montalcini, H. Meyer and V. Hamburger, In vitro experiments on the effects of mouse sarcomas 180 and 37 on the spinal sympathetic ganglia of the chick embryo, Cancer Res 14 (1954), 49–57. R. Levi-Montalcini and V. Hamburger, Selective growth stimulating effects of mouse sarcoma on the sensory and sympathetic nervous system of the chick embryos, J Exp Zool 116 (1951), 321–362. R.M. Lindsay, Adult rat brain astrocytes support survival of both NGF dependent and NGF-insensitive neurones, Nature 282 (1979), 80–82. A. Lorenzo, and B.A. Yankner, β-amyloid neurotoxicity requires fibril formation and is inhibited by congo red, Proc Natl Acad Sci USA 91 (1994), 12243–12247. L. Luo, Rho GTPases in neuronal morphogenesis, Nat Rev Neurosci 1 (2000), 173–180. Y. Luo, D. Raible and J.A. Raper, Collapsin: a protein in brain that induces the collapse and paralysis of neuronal growth cones, Cell 75 (1993), 217–227. P.C. Maisonpierre, L. Belluscio, B. Friedman, R.F. Alderson, S.J. Wiegand, M.E. Furth, R.M. Lindsav and G.D. Yancopoulos, NT-3, BDNF, and NGF’in the developing rat-nervous system: parallel as well as reciprocal patterns of expression, Neuron 5 (1990), 501–509. T.I. Mandybur, and C.C. Chuirazzi, Astrocytes and the plaques of Alzheimer’s disease, Neurology 40 (1990), 635– 639. D.M.A. Mann, N. Younis, D. Jones and R.W. Stoddart, The time course of the pathological events in Down’syndrome with particular reference to the involvement of microglial cells and deposits of β/A4, Neurodegen 1 (1992), 201–215. D.M.A. Mann, P.O. Yates, B Marcyniuk and C.R. Ravindra, The topography of plaques and tangles in Down’s syndrome patients of different ages, Neuropahtol Appl Neurobiol 12 (1986), 447–457. A. Mart´ınez, V.G. Mar´ın, S. Ramón y Cajal Junquera, R. Mart´ınez-Murillo and M. Freire, The contributions of Santi-

[83]

[84]

[85]

[86]

[87]

[88]

[89]

[90]

[91]

[92]

[93]

[94]

[95]

[96]

[97]

[98]

ago Ramón y Cajal to cancer research – 100 years on, Nature Reviews Cancer 5 (2005), 904–909. E. Masliah, M. Mallory, M. Alford, R. DeTeresa and T. Saitoh, PDGF is associated with neuronal and glial alterations of Alzheimer’s disease, Neurobiol Aging 16 (1995), 549–556. E. Masliah, A. Miller and R.D. Terry, The synaptic organization of the neocortex in Alzheimer’s disease, Med Hypotheses 41 (1993), 334–340. E. Masliah, M. Mallory, L. Hansen, M. Alford, T. Albright, R. DeTeresa, R. Terry, J. Baudier and T. Saitoh, Patterns of aberrant sprouting in Alzheimer’s disease, Neuron 6 (1991), 729–739. E. Masliah, R.D. Terry, M. Alford, R. DeTeresa and L.A. Hansen, Immunohistochemical quantification of the synapserelated protein synapthophysin in Alzheimer disease, Neurosci Lett 103 (1989), 234–239. P.L. McGeer and E.G. McGeer, The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases, Brain Res Rev 21 (1995), 195–218. P.L. McGeer, H. Akiyama, S. Itagaki and E.G. McGeer, Activation of the classical complement pathway in brain tissue of Alzheimer patients, Neurosci Lett 107 (1989), 341–346. A.C. McKee, N.W. Kowall and K.S. Kosik, Microtubular reorganization and dendritic growth response in Alzheimer’s disease, Ann Neurol 26 (1989), 652–659. L. Meda, M.A. Cassatella, G.I. Szendrei, L. Otvo Jr., P. Baron, M. Villalba, D. Ferrari and F. Rossi, Activation of microglial cells by β-amyloid protein and interferon-γ, Nature 374 (1995), 647–650. M.G. Murer, F. Boissiere, Q. Yan, S. Hunot, J. Villares, B. Faucheux, Y. Agid, E. Hirsch and R. Raisman-Vozari, An immunohistochemical study of the distribution of brainderived neurotrophic factor in the adult human brain, with particular reference to Alzheimer’s disease, Neuroscience 88 (1999), 1015–1032. R.G. Nagele, J. Wegiel, V. Venkataraman, H. Imaki, K.-C. Wang and J. Wegiel, Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease, Neurobiology of Aging 25 (2004), 663–674. S.L. Nishimura, K.P. Boylen, S. Einheber, T.A. Milner, D.M. Ramos and R. Pytela, Synaptic and glial localization of the integrin alphavbeta8 in mouse and rat brain, Brain Res 791 (1998), 271–282. K. Ohtsubo, N. Izumiyama, S. Kuzuhara, H. Mori and H. Shimada, Curly fibers are tau-positive strands in the pre- and post-synaptic neurites, consisting of paired helical filaments: observations by the freeze-etch and replica method, Acta Neuropathol (Berl) 81 (1990), 111–115. A. Patapoutian and L.F. Reichardt, Trk receptors: mediators of neurotrophin action, Curr Opin Neurobiol 11 (2001), 272– 280. M.M. Paula-Barbosa, R.M. Caradoso, M.L. Guimares and C. Cruz, Dendritic degeneration and regrowth in the cerebral cortex of patients with Alzheimers’s disease, J Neurol Sci 45 (1980), 129–134. E. Perdahl, R. Aldolfsson, I. Alafuzonff, K.A. Albert, E.J. Nestler and P. Greengard, Synapsin I (protein 1) in different brain regions in senile dementia of Alzheimer type and in multiinfarct dementia, J Neural Trans 60 (1984), 133–141. A. Perroncito, Sulla questione della rigenerazione autogena delle fibre nervose. Nota preventiva, Boll della Società Medico Chirurgica di Pavia (1905), 360–363.

V. Garc´ıa-Mar´ın et al. / Cajal’s Contributions to the Study of Alzheimer’s Disease [99]

[100]

[101]

[102] [103]

[104]

[105]

[106]

[107]

[108]

[109]

[110] [111]

[112] [113]

[114]

[115]

[116]

[117]

[118]

G. Perry, Neuritic plaques in Alzheimer disease originate from neurofibrillary tangles, Med Hypotheses 40 (1993), 257–258. G. Perry, M. Kawai, M. Tabaton, M. Onorato, P. Mulvihill, P. Richey, A. Morandi, J.A. Connolly and P. Gambetti, Neuropil threads of Alzheimer’s disease show a marked alteration of the normal cytoskeleton, J Neurosci 11 (1991), 1748–1755. C.J. Pike, A.J. Walencewicz, C.G. Glabe and C.W. Cotman, In vitro aging of β-amyloid protein causes peptide aggregation and neurotoxicity, Brain Res 563 (1991), 311–314. S. Ramón y Cajal, La rétine des vértebrés, La cellule 9 (1893), 120–255. S. Ramón y Cajal, Consideraciones Generales Sobre la Morfolog´ıa de la Célula Nerviosa, Imprenta y Librer´ıa de Nicolás Moya, Madrid, 1894. S. Ramón y Cajal, Textura del Sistema Nervioso del Hombre y de los Vertebrados, Imprenta y Librer´ıa de Nicolás Moya, Madrid, 1899–1904. S. Ramón y Cajal, Sobre un sencillo proceder de impregnación de las fibrillas interiores del protoplasma nervioso, Archivos latinos de Medicina y de Biolog´ıa 1 (1903), 1–8. S. Ramón y Cajal, Variations morphologiques, normales et pathologiques du reticule neurofibrillaire, Trab Lab Inv Biol 3 (1904), 9–15. S. Ramón y Cajal, Variations morphologiques du reticule nerveux d’invertébres et de vertébrés soumis a` l’action de contions naturelles, Trab Lab Inv Biol 3 (1904), 311–322. S. Ramón y Cajal and D. Garc´ıa, Les lesions du reticule des cellules nerveuses dans la rage, Trab Lab Inv Biol 3 (1904), 231–290. S. Ramón y Cajal, Sobre la degeneración y regeneración de los nervios, Bolet´ın del Inst. de Sueroterapia, Vacunación y Bacteriolog´ıa de Alfonso XIII 2;3 (1905), 49–60; 113–119. S. Ramón y Cajal, Mecanismo de la regeneración de los nervios, Trab Lab Inv Biol Univ Madrid 4 (1906), 119–210. S. Ramón y Cajal, Los fenómenos precoces de la degeneración traumática de los cinlindro ejes del cerebro, Trab Lab Inv Biol 9 (1911). S. Ramón y Cajal, Un nuevo proceder para la impregnación de la neurogl´ıa, Bol Soc Esp Bio 2 (1913), 104–108. S. Ramón y Cajal, Estudios sobre la degeneración y regeneración del sistema nervioso, 2 vols, Imprenta de Hijos de Nicolás Moya, Madrid, 1913–1914. S. Ramón y Cajal, Estudios sobre la degeneración y regeneración del sistema nervioso, 2 vols. (Translated and Edited by Raoul-Michel May), Oxford University Press, Humphrey Milford, London, 1928. S. Ramón y Cajal, Estudios sobre la degeneración y regeneración del sistema nervioso, 2 vols. (Translated by Raoul M. May. Edited, with and introduction & additional translations by Javier DeFelipe & Edgard G. Jones), Oxford University Press, New York, 1991. S. Ramón y Cajal, Acción neurotrópica de los epitelios (algunos detalles sobre el mecanismo genético de las ramificaciones nerviosas intraepiteliales, sensitivas y sensoriales), Trab Lab Inv Biol 17 (1919), 181–228. S. Ramón y Cajal, Manualde anatom´ıa patológica general y de bacteriolog´ıa patológica. 6th Ed. Imprenta y Librer´ıa de Nicolás Moya, Madrid, 1918. S. Ramón y Cajal, Una modificación del método de Bielschowsky para la impregnación de la neuroglia común y mesogl´ıa y algunos consejos acerca de la técnica del orosublimado, Trab Lab Inv Biol 18 (1920), 129–141.

[119] [120]

[121]

[122]

[123] [124]

[125] [126]

[127]

[128]

[129]

[130]

[131]

[132]

[133]

[134]

[135]

[136]

173

S. Ramón y Cajal, Algunas lesiones del cerebelo en un caso de demencia precoz, Trab Lab Inv Biol 24 (1926), 181–190. J. Rogers, J. Luber-Narod, S.D. Styren and W.H. Civin, Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer’s disease, Neurobiol Aging 9 (1988), 339– 349. R. Roncarati et al., The γ-secretase–generated intracellular domain of β-amyloid precursor protein binds Numb and inhibits Notch signaling, Proc Natl Acad Sci USA 99 (2002), 7102–7107. J.M. Rozemuller, P. Eikelenboom, S.T. Pals and F.C. Stam, Microglial cells around amyloid plaques in Alzheimer’s disease express leucocyte adhesion molecules of the LFA-1 family, Neurosci Lett 101 (1989), 288–292. A.B. Scheibel and U. Tomiyasu, Dendritic sprouting in Alzheimer’s presenile dementia, Expl Neurol 60 (1978), 1–8. P. Scheiffele, J. Fan, J. Choih, R. Fetter and T. Serafini, Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons, Cell 101 (2000), 657–669. T. Serafini, An old friend in a new home: cadherins at the synapse, Trends Neurosci 20 (1997), 322–323. T. Serafini, T.E. Kennedy, M.J. Galko, C. Mirzayan, T.M. Jessel and M. Tessier-Lavigne, The nectrins define a family of axon outgrowth-promoting proteins homologous to C. elegans Unc-6, Cell 78 (1994), 409–424. N. Sestan, S. Artavanis-Tsakonas and P. Rakic, Contactdependent inhibition of cortical neurite growth mediated by notch signaling, Science 286 (1999), 741–746. G. Shaw and V. Chau, Ubiquitin and microtubule-associated protein tau immunoreactivity each define distinct structures with differing distributions and solubility properties in Alzheimer brain, Proc Natl Acad Sci USA 85 (1988), 2854– 2858. J.G. Sheng, R.E. Mrak and W.S. Griffin, S100 beta protein expression in Alzheimer disease: potential role in the pathogenesis of neuritic plaques, J Neurosci Res 39 (1994), 398– 404. J.Y. Song, K. Ichtchenko, T.C. Sudhof and N. Brose, Neuroligin 1 is a postsynaptic cell-adhesion molecule of excitatory synapses, Proc Natl Acad Sci USA 96 (1999), 1100–1105. E. Spargo, P.J. Luthert, I. Janota and P.L. Lantos, β/A4 deposition in the temporal cortex of adults with Down’s syndrome, J Neurol Sci 111 (1992), 26–32. T.L. Spires, M. Meyer-Luhemann, E.A. Stern, P.J. McLean, J. Skoch, T. Nguyen, B.J. Back and T. Hymann, Dendritic Spine Abnormalities in Amyloid Precursor Protein Transgenic Mice Demonstrated by Gene Transfer and Intravital Multiphoton Microscopy, J Neurosci 25 (2005), 7278–7287. R.A. Stelzmann, H.N. Schnitzlein and F.R. Murtagh, An ¨ English translation of Alzheimer’s 1907 Paper, Uber eine eigenartige Erkankung der Hirnrinde, Clinical Anatomy 8 (1995), 429–431. E.G. Stopa, A.M. Gonzalez, R. Chorsky, R.J. Corona, J. Alvarez, E.D. Bird and A. Baird, Basic fibroblast growth factor in Alzheimer’s disease, Biochem Biophys Res Commun 171 (1990), 690–696. V. Sytnyk, I. Leshchyns’ka, M. Delling, G. Dityateva, A. Dityatev and M. Schachner, Neural cell adhesion molecule promotes accumulation of TGN organelles at sites of neuronto-neuron contacts, J Cell Biol 159 (2002), 649–661. M. Tabaton, T.I. Mandybur, G. Perry, M. Onorato, L. AutilioGambetti and P. Gambetti, The widespread alteration of neu-

174

[137]

[138]

[139]

[140]

[141]

[142]

V. Garc´ıa-Mar´ın et al. / Cajal’s Contributions to the Study of Alzheimer’s Disease rites in Alzheimer’s disease may be unrelated to amyloid deposition, Ann Neurol 26 (1989), 771–778. R.H. Tarris, M.E. Jr.Weichsel and D.A. Fisher, Synthesis and secretion of a nerve growth-stimulating factor by neonatal mouse astrocyte cells in vitro, Pediatr Res 20 (1986), 367– 372. R.D. Terry, E. Masliah, D.P. Salmon, N. Butters, R. DeTeresa, R. Hil, L.A. Hansen and R. Katzman, Physical basis of cognitive alteration in Alzheimer disease: synapse loses is the major correlate of cognitive impairment, Ann Neurol 30 (1991), 572–580. B. Urbanc, L. Cruz, S.V. Buldyrev, S. Havlin, M.C. Irizarry, H.E. Stanley and B.T. Hyman, Dynamics of Plaque Formation in Alzheimer’s Disease, Biophysical Journal 76 (1999), 1330–1334. C.E. Van der Zee, J. Fawcett and J. Diamond, Antibody to NGF inhibits collateral sprouting of septohippocam rs o owmg entorhinal cortex lesion in adult rats, J Comp Neurol 326 (1992), 91–100. J. Wegiel, K.C. Wang, M. Tarnawski and B. Lach, Microglia cells are the driving force in fibrillar plaque formation, whereas astrocytes are a leading factor in plaque degradation, Acta Neuropathol (Berl) 100 (2000), 356–364. S.R. Whittemore, L. Whittemore, L. Larkfors, T. Ebendal, V.R. Holets, A. Ericsson and H. Persson, Increased beta-nerve growth factor messenger RNA and protein levels in neonatal rat hippocampus following specific cholinergic

[143]

[144]

[145]

[146]

[147]

[148] [149]

lesions, J Neurosci 7 (1987), 244–251. M.L. Winberg, J.N. Norrdermeer, L. Tamagnone, P.M. comoglio, M.K. Spriggs, M. tessier-Lavigne and C.S. Goodman, Plexin A is a neuronal semaphorin receptor that controls axon guidance, Cell 95 (1998), 903–916. H.M. Winiewski, C. Bancher, M. Barcikowska, G.Y. Wen and J Currie, Spectrum of morphological appearance of amyloid deposits in Alzheimer’s disease, Acta Neuropathol 78 (1989), 337–347. H. Yamaguchi, Y. Nakazato, M. Shoji, S. Takatama and S. Hirai, Ultrastucture of diffuse plaques in senile dementia of the Alzheimer type: comparision with primitive plaques, Acta Neuropathol 82 (1991), 13–20. H. Yamaguchi, Y. Nakazato, S. Hirai, M. Shoji and Y. Harigaya, Electron micrograph of diffuse plaques: initial stage of senile plaque formation in the Alzheimer brain, Am J Pathol 135 (1989), 593–597. B.A. Yankner, L.K. Duffy and D.A. Kirschner, Neurotrophic and neurotoxic effects of amyloid-β protein: reversal by tachykinin neuropeptides, Science 250 (1990), 279–282. X. Yu and R.C. Malenka, Beta-catenin is critical for dendritic morphogenesis, Nat Neurosci 6 (2003), 1169–1177. J.A. Zallen, B.A. Yi and C.I. Bargmann, The conserved immunoglobulin superfamily member SAX-3/Robo directs multiple astpects of axon guidance in C. elegans, Cell 92 (1998), 217–227.