Cajal’s Contributions to the Study of Alzheimer Disease

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

Cajal’s Contributions to the Study ofAlzheimer’s Disease

Virginia Garcıa-Marın1,∗, Pablo Garcıa-Lopez1 and Miguel FreireMuseum Ramon 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, onNovember 3, Alois Alzheimer (1864–1915) presented the first case of a patient with symptoms of a disease that later wouldbe called Alzheimer’s disease. One month later, on December 10, Santiago Ramon 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 seemnot to be related, but working in the Museum Cajal we found 37 histological preparations of material from patients sufferingfrom Alzheimer’s disease, revealing that Cajal also studied this disease. This paper deals with Cajal’s contribution to the studyof 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

Ramon y Cajal is broadly known by his studies ofthe anatomy, functional organization and developmentof the nervous system. However, his observations andtheories on pathology of the nervous systems are littleknown, with the exception of his experimental stud-ies about degeneration and regeneration of the ner-vous system [113]. Cajal made important contribu-tions to pathological anatomy including his studies oncancer [82], Alzheimer’s disease (AD), neurosyphilis,Korsakoff’s syndrome, and rabies.

AD is one of the most important neurological disor-ders. Since it was discovered by Alzheimer in 1906,much research has been done in order to clarify themechanism that underlies the disease. Cajal also paidattention to this disorder and following his own re-search about degeneration and regeneration of the ner-vous system gave some ideas about the degenerativeand regenerative processes that occur in AD.

Our aim is to study the original histological prepara-tions conserved in the Museum Cajal from patients suf-

1These 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 themain pathological hallmarks of AD taken from theseslides, and review some of Cajal’s ideas about ADfrom a historical and present-day perspective. Cajal’smain contributions to AD are summarized in his Span-ish booksDegeneracion y Regeneracion del sistemanervioso2 [113] andManual General de Anatomia pa-tologica y bacteriologıa 3 [117].

CAJAL’S HISTOLOGICAL PREPARATIONS

In the Museum Cajal, 4,529 histological preparationsof Cajal are conserved, 690 are related to pathology:cancer (92 slides), degeneration and regeneration of thenervous system (391), AD (37), neurosyphilis (135),Korsakoff syndrome (17) and rage (18). Among Cajal’shistological preparations of AD (Fig. 1), we have founddifferent histological methods. Table 1 summarizes thedifferent components of each method and their mainstaining targets. Cajal used to write on the labels of his

2This book has been translated into English in 1928 (translationby May) [114] and 1991 (translation by translation by May, withintroduction and additional translation by DeFelipe and Jones) [115].

3Not English version of this book.

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

V. Garcıa-Marın et al. / Cajal’s Contributions to the Study of Alzheimer’s Disease 167

Box 1

Cajal proposed his neurotropic hypothesis, firstly named chymiotactic hypothesis in 1893 [102]. He proposed the existence of neurotropicsubstances for explaining the guidance of axons to their targets during development. Cajal also admitted the secretion of neurotropicsubstances by intermediate targets. For instance, he explained the attraction of commissural axons to the ventral part of the epithelial barrelduring 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 possibil-ity [113]. However this Cajal’s concept of neurotropic substance evolved to a concept of neurotrophic agents especially under pathologicalconditions, in which the substances secreted by the Schwann cells would create the trophic ambient necessary for the growing of the axonalsprouts.“These substances have not only an orientating function, but they are also trophic in character, since the sprouts that have arrived at theperipheral stump are robust, show a great capacity for ramification and grow straight to their target without vacillations, as though they werefollowing an irresistible attraction”[113].Nowadays, this double concept of Cajal is still valuable for developing and regenerating nervous system, i) the growth and maturation ofcells, 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 includedsurface-bound adhesive molecules.As examples of neurotrophic substances which allowed the growth and maturation are found neurotrophins such as; NGF [72,73], BD-NF [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] /plexins-Neuropilin [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], neurexin-neuroligin [124,130] and syndecan 2 [38,58].

More studies focused on nerve growth factors arenecessary to understand the mechanism of neurode-generative disorders and their treatment. In additiongrowth factors constitute a therapeutic approach for thetreatment of the disease.

Neurofibrillary pathology

Neurofibrillary tangles were described by Alzhei-mer [3]. At Cajal’s time, scientists called them “Alzhei-mer lesions” as we can see in Cajal’s preparations(Fig. 1) and writings [117]. Alzheimer wrote “Speci-mens which were prepared according to Bielschowsky’ssilver method show very striking changes of the neu-rofibrils. Inside of a cell which appears to be quitenormal, one or several fibrils can be distinguished bytheir unique thickness and capacity for impregnation.Further examination shows many fibrils located nextto each other which have been changed in the sameway. Next, combined in thick bundles, they appear oneby one at the surface of the cell. Finally, the nucleusand the cell itself disintegrate and only a tangle of fib-rils indicates the place where a neuron was previouslylocated” (Fig. 5J) [3,53,133]. Interestingly, Cajal alsoobserved neurofibrillar alterations in physiological andpathological conditions such as hibernation, rage, orafter a wound in the nervous system (Box 2).

The different morphological variants of tanglesfound are in part due to the nature of the neurons inwhich they were formed. Flame-shaped NFT are char-acteristic of pyramidal neurons, and globose NFT are

found in large non-pyramidal neurons [34]. The flame-shaped NFT sometimes have a great apical process thatfollows the direction of the apical dendrite (Fig. 5D–F).

In addition, we have found other lesions related toneurofibrillary degeneration, neuropil threads and dys-trophic neurites. Neuropil threads are short and tortu-ous argyrophilic neurites dispersed in the neuropil thatare immunoreactive for tau [21]. Most neuropil threadsare probably derived from dendritic processes [20], butup to 10% have been identified as myelinated axonswith electron microscopy [94,100]. Dystrophic neu-rites appear surrounding the corona of neuritic senileplaques (Fig. 4). These dystrophic neurites could be thecrown of nervous budswhich Cajal refers to in 1918.Cajal specially proposed that these dystrophic neuriteswere axonal sprouts with terminal clubs directed tothe plaque because the influence of some neurotrop-ic substances. Interestingly these axonal sprouts werefirstly seen by Cajal in regenerating axonal process af-ter the section of the sciatic nerve (Fig. 7) [109,110]and also confirmed by Perroncito [98]. In addition tothe axonal sprouting [45,46,59,84,85],dendritic sprout-ing [6–9,41,60,71,89,96,123] have been confirmed inAD. This process of dendritic regeneration is mediat-ed by structures that resemble dendritic growth conesInterestingly dendritic neoformation was observed byCajal [110] in the sensitive ganglion of old humans anddogs and in the hippocampus of old dogs by RodriguezLafora [71], disciple of Cajal and Alzheimer.

The regeneration studies of Cajal influenced the ini-tial studies of AD. Fischer proposed that the senile


modify its own structural organization and functioningsas an adaptative response to functional demands whichis impaired in AD” [5]. Coming back to Cajal and theloss of plasticity in the adult brain he stated: “Suchplasticity of the cellular processes probably varies atdifferent ages: greater in the young man, diminishedin the adult and almost completely disappeared in theaged” [31,103].

GLIAL ALTERATION

Cajal observed that astrocytes in the senile plaquesshowed hypertrophy in their bodies and appendages,and that some of these processes ended in balls [117].This hypertrophy of astrocytes is clear in his histolog-ical preparations (Fig. 6), some of them are extremelybig and show a great quantity of gliofilaments as wasfirstly noticed by Alzheimer in his famous report of Au-guste, D. [3] “The glia have developed numerous fibersand other glial cells have large lipid droplets”. Astro-cytes acquire a fibrous character like the astrocytes inwhite matter. The processes of the astrocytes surroundthe senile plaques. Mature senile plaques are not onlywrapped by astrocytic processes, but they also pene-trate the plaque core [79,92]. Astrocytes secrete growthfactors such as nerve growth factor (NGF), basic fi-broblast growth factor (BFGF), etc. which are essentialfor survival and terminal remodeling of the survivingneurons because they act as a trophic stimulus inducingaxonal growth and sprouting [74,137,140,142].

Furthermore, in AD there is an alteration in mi-croglial cells, with hypertrophy and changes in theirmorphology towards round-shaped macrophage-likecells. Microglial cells were found surrounding senileplaques (Fig. 6B–C, E). Activated microglia are mostevident in dense cored plaques [10,141]. These mi-croglia have a very important role in the process of in-flammation as Fischer point out in 1910. He thoughtthat “the foreign substance” provoked the neuroregen-erative response by inflammation, although he couldnot find morphological signs of an inflammation pro-cess around the plaques. In the eighties of the lastcentury using monoclonals antibodies directed againstcells of the monocyte-macrophage cell lineage, senileplaques were shown to be associated with clusters ofactivated microglia [88,120,122]. The neuroinflamma-tory response includes a local upregulation of acute-phase proteins, complement, cytokines and other in-flammatory mediators [2]. However the diffuse plaquesare no associated with activated microglia

CONCLUSIONS

Cajal described his findings about AD more than 10years later than Alzheimer published his first article in1907. However, it is still useful to review his slidesand writings in order to compare them with the actualknowledge about the disease and also to point out someof the ideas proposed by Cajal.

The staining methods used by Cajal, such as reducedsilver nitrate, sublimated gold chloride, ammoniacalsilver oxide, and the Bielschowsky method, are veryuseful to observe the many alterations in AD. Am-moniacal silver oxide and the Bielschowsky methodsgive a general idea of the brain alterations because theystain senile plaques, neurofibrillar lesions, reactive mi-croglia, and active astrocytes. The reduced silver ni-trate method is very useful to observe the evolutionof the senile plaques, and finally, the sublimated goldchloride method allows a specific study of reactive as-trocytes. These classic staining methods can still beuseful in the research of this pathology, because todaywe can re-interpret them taking into account the knowl-edge acquired using specific antibodies. Furthermore,with the use of specific antibodies only we may looseand overlook other components of the senile plaquesand neurofibrillary tangles already shown by the clas-sical staining methods.

The original works of the pioneers and Cajal in thestudy of AD still propose hypotheses and questions thatwe have to corroborate and/or to answer to be able toadvance the knowledge of AD. For instance, Cajal pro-posed in the evolution of senile plaques a degenerationof neurites in the surrounding area. Nowadays withmodern technique it has been observed disruptions inneurites trajectories and reductions in dendritic spinedensity in the regions near the plaques have been ob-served. The dystrophic neurites (both axonal and den-dritic origin) present swellings on their structure thatwas observed by Cajal with his silver nitrate method aswe can see in his drawing. Moreover, Cajal suggestedthat axonal sprouts could be attracted towards the re-gion of the plaque, under the influence of some specialneurotropic substance. Future research should clari-fy these issues in order to advance in the knowledgeof AD.

ACKNOWLEGDEMENTS

We acknowledge Santiago Ramon y Cajal Junquerafor his help studying the histological preparations and

170 V. Garcıa-Marın et al. / Cajal’s Contributions to the Study of Alzheimer’s Disease

Isidro Ferrer for his useful advices. Original drawingsfrom the Museum Cajal are reproduced with permissionfrom the Inheritors of Santiago Ramon y Cajal . Theauthors are supported by the Spanish Ministry of Health(ISCIII, PI04/0594) and the Areces Foundation.

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Cajal’s Contributions to the Study of Alzheimer Disease