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Journal of Alzheimer’s Disease xx (20xx) x–xx DOI 10.3233/JAD-132660 IOS Press
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Golgi Apparatus and Protein Trafficking in Alzheimer’s Disease
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Stavros J. Baloyannis*
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Department of Neurology, Aristotelian University, Thessaloniki, Greece
Accepted 18 April 2014
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Keywords: Alzheimer’s disease, electron microscopy, Golgi apparatus, proteins trafficking
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INTRODUCTION
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Alzheimer’s disease (AD) is a progressive degeneration of the brain, which has been recognized as the main causative factor of decline of mental faculties in senility [1]. The clinical manifestations of the disease are characterized by the insidious onset, the variability in its clinical presentation [2, 3], and the continuous deterioration of the mental faculties, as time advances, involving memory and learning impairment [4], language disturbances, visuo-spatial disorientation, behavioral disturbances, depressive symptoms [5], and personality changes [6–8].
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Abstract. Alzheimer’s disease (AD) is a progressive degeneration of the brain, inducing memory decline, inability in learning, and behavioral alterations, resulting progressively in a marked deterioration of all mental activities and eventually a vegetative state. The main causative factor, however, is still unclear. The implication of amyloid-, APP, tau protein, the selective loss of neurons, the alteration of the synapses, the cytoskeletal changes, and the morphological alterations of the brain capillaries contribute substantially to the pathogenetic profile of the disease, without sufficiently enlightening the initial steps of the pathological procedures. The ultrastructure of the neuronal organelles as well as histochemical studies revealed substantial alterations, primarily concerning mitochondria. In this study, the morphological and morphometric alterations of the Golgi apparatus (GA) are described in the Purkinje cells of the cerebellum in twenty AD brains, studied with electron microscopy. As it is well established, GA has a very important role to play in many procedures such as glycosylation, sulfation, and proteolysis of protein systems, which are synthesized in the endoplasmic reticulum of nerve cells and glia. GA may also play a crucial role in protein trafficking and in misfolding of protein aggregates. In addition, the hyperphosphorylation of tau protein is closely related with the pathology of GA. In AD cases, described in this study, an obvious fragmentation of the cisternae of GA was observed in the Purkinje cells of the vermis and the cerebellar hemispheres. This alteration of GA may be associated with alterations of microtubules, impaired protein trafficking, and dendritic, spinal, and synaptic pathology, since protein trafficking plays an essential role in the three dimensional organization of the dendritic arbor and in the integrity of the synaptic components.
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∗ Correspondence
to: Stavros J. Baloyannis, MD, PhD, Angelaki 5, 546 21 Thessaloniki, Greece. Tel.: +30 2310270434; Mobile: 30 6944418079; Fax: +30 2310270434; E-mail: [email protected].
The pathological profile of AD is characterized mainly (a) by the abnormal deposition of amyloid- (A) in the brain (the amyloid cascade hypothesis) [9], mostly as neuritic plaques, which show high variability concerning their distribution; and (b) by tau pathology, synthesizing neurofibrillary tangles in vulnerable brain regions, such as the dentate gyrus of the hippocampus and the amygdala, as well as the deep layers of the temporal isocortex and the cortices of the frontal and parietal lobes, which appear to be most affected in the initial stages of AD. The evolution of AD pathology in various area of the brain at several stages of the disease was described in autopsy material by Braak and Braak [10]. A definite diagnosis of AD may be determined (a) by the gradual decline in cognitive function, proved by history and neuropsychological testing, and (b) by the presence of AD pathology, such as tangles and plaques
ISSN 1387-2877/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved
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temporal, parietal, and frontal cortices. It is reasonable that alterations of GA may be of substantial importance in plotting the pathogenetic background of AD [32, 33], since GA is associated with protein trafficking, and proteins destined for axonal transport system, dendritic flow, and synapses are processed through the components of the Golgi complex [34]. Impairment of intracellular trafficking and proteolysis of APP are very important issues for the pathogenesis of AD [35], in view that the trafficking of APP involves the endocytic pathway, where the amyloidogenic process may occur by the action of ␣- and -secretases [35, 36]. The present study seeks to correlate the ultrastructural changes of the trafficking pathways with the synaptic pathology in the molecular, Purkinje cell, and granular cell layers of the cerebellar cortex in early cases of sporadic AD, where A deposits are minimal and neurofibrillary tangles are rarely seen. It is well documented [37] that the cerebellum is mostly affected in familial AD, where Purkinje cell density is significantly decreased, whereas in sporadic AD cases, Purkinje cell loss is usually minimal. On the other hand, Purkinje cells are characterized by long dendrites, extensive dendritic arborization, and innumerable dendritic spines [38], therefore enabling a clear and efficient correlation between alteration of GA, protein trafficking, and synaptic changes in AD disease. It is assumed that a further approach to pathogenic complexity of AD might be essential for preventing the onset of a disease which eventually induces so many serious clinical, ethical, social, and economic problems.
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in the medial temporal lobe and the cortex of the brain hemispheres [11, 12]. The substantial component of the neuritic plaques is recognized to be A [13], which is a cleavage product of the amyloid- protein precursor (APP) [14]. In addition the tremendous synaptic loss plots the morphological profile of the disease, also playing the most crucial role in the mental decline of suffering persons, resulting in dementia. Widespread cortical neuronal loss fulfills the pathological pattern of the disease, being particularly excessive in cases with an earlier onset. According to amyloid cascade hypothesis [9], A is the most important causative factor either in familial or in sporadic type of AD [15, 16], in view that its oligomer forms are characterized by excessive toxicity [17]. It is hypothesized that a chronic disequilibrium and instability between the production and clearance of A in addition to its misfolding may lead, step by step, to synaptic alterations and glial activation [15]. The discovery of familial AD mutations in the APP gene [18] underlines the substantial role that APP integrity, trafficking, and metabolism may play in the wide spectrum of pathogenic potential factors in AD. However, the etiopathogenic mechanisms of the sporadic cases of the disease remain unknown in spite of constantly ongoing research. The deposition of A and the hyperphosphorylation of tau protein have been recognized as the main procedures that lead to the generation of neuritic plaques and neurofibrillary tangles, which are the principal pathognomonic postmortem diagnostic criteria of AD. A is derived from APP, a member of the nexins encoded on chromosome 21, which undergoes proteolysis by combined effects of - and ␥-secretases [19], resulting in the formation of 39 to 43 amino-acid peptides, which are deposited forming the basis of the neuritic plaques. In addition, oxidative stress is a dominant factor in the pathogenesis of AD [20], associated with morphological alterations of mitochondria, which are observed at any area of the brain including the cortex, the subcortical centers, and the cerebellar cortex [20–23]. It is well documented that morphological and functional alterations of mitochondria may also occur in a considerable number of degenerative disorders of the brain [24–29], associated frequently with oxidative stress [27, 30, 31] and vascular changes [31]. Morphological alterations of Golgi apparatus (GA) have been observed in nerve cells even in the initial stages of AD, when neurofibrillary tangles and neuritic plaques are still rare, seen mostly in the hippocampus and in a limited proportion of nerve cells in the
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MATERIAL AND METHODS
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The cortex of the vermis and the cerebellar hemispheres of twenty patients who suffered from AD, twelve men and eight women, aged 62–90 years, were studied in light and electron microscopy (Table 1). The patients fulfilled all the current neuropsychological, clinical, and laboratory diagnostic criteria of AD. The mean education of the patients was 16 years. They had sufficient fluency in speaking their native language. Two of the patients were bilingual. Screening procedures were applied, which included medical history, medical examination, cardiological investigation, physical neurologic assessment, psychiatric examination, and neuropsychological testing. Clinical and laboratory investigation of the patients included carotid duplex Doppler, computerized
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Braak and Braak stage
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II/III II II/III II/III III II/III II/III III II/III III II/III II/III II/III III II/III II/III III II/III III IV
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Electron microscopy
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The study of the cytoarchitecture of the cortex of the cerebellum, evaluation of dendritic arborization of neurons, morphometric estimation of dendritic branches, estimation of morphology, and density of dendritic spines were performed in light microscopy on thick sections stained according to rapid Golgi method (Fig. 1). For this reason, the remaining parts of the cerebellar cortex, after a long fixation in formalin, were processed for silver impregnation, according to rapid Golgi technique, which consisted of immersion of the tissue in potassium dichromate (7 g potassium dichromate in 300 mL water) for 10 days and post immersion in 1% silver nitrate for 10 days. Then the specimens
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tomography scanning, single-photon emission computed tomography, magnetic resonance imaging of the brain, and electroencephalography. Neuropsychological testing included Mini-Mental State Examination, Alzheimer’s Disease Assessment Scale-Cognitive Subscale, and Dementia Rating Scale [39]. The patients passed away from heart arrest; twelve of them had myocardial infarction one to nine months after the last clinical and laboratory evaluation. Eight of them were pronounced dead after sleep. The postmortem examination was performed soon after death within approximately 6 hours. In addition, we used ten brains apparently unremarkable, derived from healthy individuals of the same age range as the AD patients, who died accidentally, as normal controls.
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The thin sections were prepared in a Reichert Ultratome. Then the sections on the grids were contrasted with uranyl acetate and lead citrate, and the fine structure of the specimens was studied in a Zeiss electron microscope of the type 9aS. The study was particularly focused on the morphology of the organelles of the neurons, such as mitochondria, GA, endoplasmic reticulum, and endosomes. In addition, the study also focused on dendritic profiles, spines, axons, axonic collaterals, and synaptic components. The morphometric estimation at the level of electron microscopy was carried out on micrographs of a standard magnification of 56,000 X.
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Table 1 List of the AD brains included in the study. Thirty samples of each one of them from the vermis and the cerebellar hemispheres were studied in electron microscope from 1974 to 2011
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Samples of a small size (2 × 2 × 2 mm) were excised from various areas of the cortex of the vermis and the hemispheres of the cerebellum and immersed immediately in Sotelo’s fixing solution, which consisted of 1% paraformaldehyde, 2.5% glutaraldehyde in cacodylate buffer 0.1 M, adjusted at pH 7.35. Then all the specimens were postfixed by immersion in 1% osmium tetroxide for 30 min at 16◦ C and had undergone dehydration by immersion in graded alcohol solutions and propylene oxide.
Fig. 1. Purkinje cells (PC) from the uvula of the vermis of an AD case (Male 72 y). The limitation of the dendritic arborization is obvious. Golgi silver impregnation technique (Magnification = 1,200X, bar = 50 m).
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Statistical analysis
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RESULTS
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Electron microscopy is the most efficient method for observation, morphological and morphometric study, and evaluation of the organelles of the neuronal perikaryon, dendritic profiles, spines, synapses, neuron-glial relationships, and morphology of the capillaries in the brain in normal and pathological conditions. The study in electron microscopy revealed dilatation of the cisternae of the smooth endoplasmic reticulum and substantial fragmentation of the cisternae of GA in numerous Purkinje cells of the cerebellar cortex (Fig. 2). The cisternae of the GA were shorter in correlation to normal controls. Fragmentation of the cisternae of GA was also observed in granule cells in the vermis and the cerebellar hemispheres. It is worth emphasizing that the alterations of GA were also noticed in neurons without findings of tau pathology and in areas with minimal extracellular deposits
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Fig. 2. Purkinje cell from the inferior semilunar lobe of the cerebellar hemisphere of an AD case (Female 76 y). The dilatation of the cisternae of the GA and the alteration of the mitochondria are prominent in the perikaryon of the neuron. Electron micrograph (Magnification = 20,000X, bar = 0.2 m).
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Statistical evaluation was based on the Student’s ttest. 5,000 mitochondria and 600 GA were studied from 30 specimens of each one of the 20 AD brains and correlated with equal number of mitochondria and GA from 30 specimens of each one of the 10 normal controls. All the micrographs were studied and analyzed in the same way. Significance was taken as p < 0.05.
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underwent rapid dehydration by short immersion in graded alcohol solutions and embedded in paraffin. Thirty sections of each one of the specimens were prepared, at an alternative thickness of 100 m and 25 m. From each one of the specimens, thirty sections of 25 m were processed according to Golgi-Nissl technique by post-staining with methylene blue. In addition, samples were taken from hippocampus and temporal, frontal, parietal, and occipital lobes and were processed for Bodian staining, in order to obtain a global neuropathological estimation of AD lesions. After mounting in Permount, the sections were studied in a photomicroscope (Zeiss Axiolab). Neuropathological alterations were estimated and rated according to Braak and Braak staging [10, 40] and CERAD neuritic plaque score [41, 42]. The consensus recommendations concerning the neuropathological diagnosis of AD introduced by the National Institute on Aging and the Reagan Institute [43] were also respected.
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Fig. 3. Fragmentation of the cisternae of Golgi apparatus (GA), of a Purkinje cell from the uvula of the vermis of an AD case (Male 72 y). Electron micrograph (Magnification = 128,000X, bar = 0.1 m).
of A (Fig. 3). The number of the vacuoles and vesicles, which are associated with the Golgi complex, was reduced in most Purkinje and granule cells of the cerebellum. Since vacuolization of the cell body was not
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noticed in the majority of neurons, we may hypothesize that the alterations of the GA may occur quite independently from the cytoplasmic vacuolization. It has to be underlined that alterations of GA were also observed in the soma of astrocytes (Fig. 4) and in endothelial cells as well as in the pericytes of patients suffering from AD. Mitochondrial pathology was observed in the soma and dendrites and in a large number of spines of dendritic branches in all of the studied specimens (Fig. 5). Pathological findings consisted of (a) a considerable change of the shape and size of mitochondria, (b) fragmentation of mitochondrial cristae and (c) accumulation of osmiophilic material in a substantial number of mitochondria. In many dendritic branches, mitochondria showed unusual polymorphism, such as concentric arrangement of the cristae or arrangement of cristae according to the major diameter of the organelle. In numerous climbing fibers, mitochondria were seen as very elongated and packed together in large numbers. Many round mitochondria of a short diameter were intermixed with dense bodies. Morphological alterations of mitochondria coexisted with the changes of the shape and size of the cisternae of the GA and the alterations of microtubules, which were roughly dispersed in the perykarion and dendritic profiles of Purkinje cells in AD brains (Fig. 6). Morphometric estimation of Purkinje cell mitochondria in normal control brains revealed that long ellipsoid mitochondria in the spines have an average diameter of 650 ± 250 nm and a mean axial ratio of 1.9 ± 0.2 (p < 0.005), whereas small round mitochondria
Fig. 5. Dendritic profile of a Purkinje cell in the molecular layer of the nodule in an AD case (Male 78 y). Numerous twisted microtubules (MT) are seen intermixed with abnormal mitochondria. Abnormal synaptic profiles (S) are seen on the surface of the dendritic branch. Electron micrograph (Magnification = 28,000X, bar = 0.3 m).
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Fig. 4. Fragmentation of the cisternae of Golgi apparatus (GA), abnormal mitochondria (M), dense bodies (DB), and lysosomes in a Bergmann’s glial cell of the superior semilunar lobe of the cerebellum of an AD case (Male 80 y). Electron micrograph (Magnification = 36, 000X, bar = 0.3 m).
Fig. 6. Small round mitochondria (M), dense bodies, and atypically dispersed microtubules and endocytotic vesicles (EV) are seen in the perikaryon of Purkinje cell of the nodule in an AD case (Male 82 y). Electron micrograph (Magnification = 128,000X bar = 0.03 m).
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Fig. 8. A mossy fiber (MF) terminal in the granule layer of the superior semilunar lobe of the cerebellum in an AD case (Female 85 y). The electron microscope reveals a marked polymorphism and pleomorphism of the dramatically decreased synaptic vesicles and the presence of multivesicular body (MVB). Electron micrograph (Magnification = 200,000X, bar = 0.02 m).
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have a mean radius of 350 nm. The mean diameter of ellipsoid mitochondria in AD brains was estimated at 480 ± 250 nm (p < 0.005) and the mean axial ratio was 1.7 ± 0.2 nm (p < 0.005). The small global mitochondria appear to have a mean radius of 280 nm. Many polymorphic endocytotic vesicles were also observed in Purkinje cells and granule cells, and in endothelial cells and pericytes of the capillaries of the cerebellar cortex. Thick perivascular astrocytic processes were seen including numerous large pinocytotic vesicles. In addition, electron microscopy revealed morphological alterations of spines and a considerable decrease in spine density, mostly concerning secondary and tertiary Purkinje cell dendritic branches (Fig. 7). Many spines contained large multivesicular bodies, abnormal polymorphic mitochondria, and atypical spine apparatus. Many abnormal giant spines emerged from terminal Purkinje cell dendritic branches. Several presynaptic terminals of parallel and mossy fibers in the cerebellum of AD brains were characterized by polymorphism and pleomorphism of the limited synaptic vesicles (Fig. 8). Astrocytic proliferation was also prominent both in the vermis and the cerebellar hemispheres, also demonstrating abnormal elongated mitochondria and fragmented cisternae of GA.
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Fig. 7. Synaptic profile between parallel fiber (PF) and Purkinje cell dendritc spine (DS) in the molecular layer of the superior semilunar lobe of the cerebellum in an AD case (Male 82 y). Poverty and pleomorphism of synaptic vesicles (sv) is obvious. Electron micrograph (Magnification = 167,000X, bar = 0.04 m).
DISCUSSION Protein trafficking is a continuous process in neurons either in normal or in pathological conditions. Any abnormal modification or deviation of protein trafficking may be crucial in inducing a stream of phenomena which may lead to serious disorders. APP is a ubiquitous Type 1 membrane glycoprotein, which is continuously trafficking in nerve cells [44], soma, and dendrites and along central and peripheral axons in an anterograde way. APP, during its trafficking to the cell surface and in the endocytic pathway, generates A, ranging in size from 37 to 43 amino acids, by cleavage of the APP C terminal fragment. APP, on the other hand, undergoes sequential cleavages by two intramembranous proteases, namely -secretase (BACE-1), which has its active site in the lumen [45], and ␥-secretase, which contains presenilin (PS), nicastrin, Aph-1, and the Pen-2 [46] proteins. Amyloidogenic activity may also occur in the endocytic pathway of APP [36], since BACE-1 localizes to the Golgi and endosomes, expressing the highest activity in the endosomal compartments [47]. In addition, APP undergoes secretory cleavages by metalloproteases [48]. The generated soluble oligomers of A
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neuronal interactions, is also related to down regulation of APP, which results in increased endocytosis of nerve growth factor and nerve growth factor receptors [75]. However BACE1, which is responsible for -secretase cleavage of APP, trafficking in neuronal recycling endosomes [76] might be related to presynaptic production of A, being reasonably involved in the pathogenic mechanism of AD [77]. It is also known that A may increase the production of reactive oxygen species [78] in the mitochondria, which in turn may seriously affect mitochondrial function [79], a fact which may further induce synaptic degeneration in AD [80], since many dendritic branches and abnormal spines were seen including unusual polymorphic mitochondria [23]. Morphological alterations of mitochondria are associated with a decrease of mitochondrial energy production, which in turn increases APP amyloidogenic activity [81] and induces synaptic degeneration [82] and a substantial decrease of spine density in the dendritic profiles [23]. DISCLOSURE STATEMENT The author’s disclosure is available online (http:// www.j-alz.com/disclosures/view.php?id=2285).
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are considered as substantial etiological component in the pathogenesis of AD [49]. GA may have a substantial contribution in the trafficking of APP and the amyloidogenic process. The morphological changes of GA, which are noticed even in the initial stages of AD, plead in favor of the hypothesis that impairment of trafficking in Golgi cisternae and the endosomes may be crucial factors in amyloidogenesis. In addition, the low density lipoprotein receptor-related protein (LRP), which is cleaved by furin inside the trans-Golgi network, may play a substantial role in mediating ligand internalization [50, 51], since many ligands may bind LRP [52]. Additionally, PS1, which is a component of ␥-secretase, is mainly located in the endoplasmic reticulum, cisternae of GA [53], and synapses, where it associates with the cadherin/catenin adhesion complex [54]. In familial cases of AD, mutations in PS1 induce a substantial increase in the formation of A42 , contributing decisively in the pathogenic process of the disease [55]. It is worth to mention that PS1 is associated with cytoskeleton [56] and also may play a role in the trafficking of N-cadherin to the plasma membrane [57], a procedure which is crucial for synaptic activity, since N-cadherin is localized at the synapses, providing an adhesive force across the synaptic cleft [58, 59]. In addition, the overexpression of PS1 may result in decreasing sialysation of the cell surface protein NCAM, which has been implicated, among the others, in synaptic plasticity and axonal outgrowth [60]. At the same time, mutant forms of the PS1 protein may alter glycoprotein processing [61] as well as lysosomal proteolysis and autophagy [62]. Alterations of GA may have an essential effect in protein glycosylation, since the trans-Golgi network is associated with the catalysis of soluble glycoproteins [63, 64]. In fact, glycosylation of proteins is among the major processing activities of the GA, which occurs through a large number of sequential steps, each requiring its own enzymes [65]. It is also well established by immunocytochemical and morphometric studies in amyotrophic lateral sclerosis, AD, and aging, that GA is a reliable index of activity or degeneration and aging [32, 66–69]. The fragmentation of GA may also affect dendritic protein trafficking, which plays a very important role in dendritic remodeling or arbor stability, since microtubules and microtubule associated proteins are closely associated with Golgi outpost and trafficking of vesicles and proteins to terminal dendritic branches and spines [70–74]. The plasticity of the dendrites, axons, and synapses, which is an essential procedure for remodeling of
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Journal of Alzheimer’s Disease xx (20xx) x–xx DOI 10.3233/JAD-132660 IOS Press
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Golgi Apparatus and Protein Trafficking in Alzheimer’s Disease
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Stavros J. Baloyannis*
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Department of Neurology, Aristotelian University, Thessaloniki, Greece
Accepted 18 April 2014
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Keywords: Alzheimer’s disease, electron microscopy, Golgi apparatus, proteins trafficking
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INTRODUCTION
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Alzheimer’s disease (AD) is a progressive degeneration of the brain, which has been recognized as the main causative factor of decline of mental faculties in senility [1]. The clinical manifestations of the disease are characterized by the insidious onset, the variability in its clinical presentation [2, 3], and the continuous deterioration of the mental faculties, as time advances, involving memory and learning impairment [4], language disturbances, visuo-spatial disorientation, behavioral disturbances, depressive symptoms [5], and personality changes [6–8].
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Abstract. Alzheimer’s disease (AD) is a progressive degeneration of the brain, inducing memory decline, inability in learning, and behavioral alterations, resulting progressively in a marked deterioration of all mental activities and eventually a vegetative state. The main causative factor, however, is still unclear. The implication of amyloid-, APP, tau protein, the selective loss of neurons, the alteration of the synapses, the cytoskeletal changes, and the morphological alterations of the brain capillaries contribute substantially to the pathogenetic profile of the disease, without sufficiently enlightening the initial steps of the pathological procedures. The ultrastructure of the neuronal organelles as well as histochemical studies revealed substantial alterations, primarily concerning mitochondria. In this study, the morphological and morphometric alterations of the Golgi apparatus (GA) are described in the Purkinje cells of the cerebellum in twenty AD brains, studied with electron microscopy. As it is well established, GA has a very important role to play in many procedures such as glycosylation, sulfation, and proteolysis of protein systems, which are synthesized in the endoplasmic reticulum of nerve cells and glia. GA may also play a crucial role in protein trafficking and in misfolding of protein aggregates. In addition, the hyperphosphorylation of tau protein is closely related with the pathology of GA. In AD cases, described in this study, an obvious fragmentation of the cisternae of GA was observed in the Purkinje cells of the vermis and the cerebellar hemispheres. This alteration of GA may be associated with alterations of microtubules, impaired protein trafficking, and dendritic, spinal, and synaptic pathology, since protein trafficking plays an essential role in the three dimensional organization of the dendritic arbor and in the integrity of the synaptic components.
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∗ Correspondence
to: Stavros J. Baloyannis, MD, PhD, Angelaki 5, 546 21 Thessaloniki, Greece. Tel.: +30 2310270434; Mobile: 30 6944418079; Fax: +30 2310270434; E-mail: [email protected].
The pathological profile of AD is characterized mainly (a) by the abnormal deposition of amyloid- (A) in the brain (the amyloid cascade hypothesis) [9], mostly as neuritic plaques, which show high variability concerning their distribution; and (b) by tau pathology, synthesizing neurofibrillary tangles in vulnerable brain regions, such as the dentate gyrus of the hippocampus and the amygdala, as well as the deep layers of the temporal isocortex and the cortices of the frontal and parietal lobes, which appear to be most affected in the initial stages of AD. The evolution of AD pathology in various area of the brain at several stages of the disease was described in autopsy material by Braak and Braak [10]. A definite diagnosis of AD may be determined (a) by the gradual decline in cognitive function, proved by history and neuropsychological testing, and (b) by the presence of AD pathology, such as tangles and plaques
ISSN 1387-2877/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved
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temporal, parietal, and frontal cortices. It is reasonable that alterations of GA may be of substantial importance in plotting the pathogenetic background of AD [32, 33], since GA is associated with protein trafficking, and proteins destined for axonal transport system, dendritic flow, and synapses are processed through the components of the Golgi complex [34]. Impairment of intracellular trafficking and proteolysis of APP are very important issues for the pathogenesis of AD [35], in view that the trafficking of APP involves the endocytic pathway, where the amyloidogenic process may occur by the action of ␣- and -secretases [35, 36]. The present study seeks to correlate the ultrastructural changes of the trafficking pathways with the synaptic pathology in the molecular, Purkinje cell, and granular cell layers of the cerebellar cortex in early cases of sporadic AD, where A deposits are minimal and neurofibrillary tangles are rarely seen. It is well documented [37] that the cerebellum is mostly affected in familial AD, where Purkinje cell density is significantly decreased, whereas in sporadic AD cases, Purkinje cell loss is usually minimal. On the other hand, Purkinje cells are characterized by long dendrites, extensive dendritic arborization, and innumerable dendritic spines [38], therefore enabling a clear and efficient correlation between alteration of GA, protein trafficking, and synaptic changes in AD disease. It is assumed that a further approach to pathogenic complexity of AD might be essential for preventing the onset of a disease which eventually induces so many serious clinical, ethical, social, and economic problems.
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in the medial temporal lobe and the cortex of the brain hemispheres [11, 12]. The substantial component of the neuritic plaques is recognized to be A [13], which is a cleavage product of the amyloid- protein precursor (APP) [14]. In addition the tremendous synaptic loss plots the morphological profile of the disease, also playing the most crucial role in the mental decline of suffering persons, resulting in dementia. Widespread cortical neuronal loss fulfills the pathological pattern of the disease, being particularly excessive in cases with an earlier onset. According to amyloid cascade hypothesis [9], A is the most important causative factor either in familial or in sporadic type of AD [15, 16], in view that its oligomer forms are characterized by excessive toxicity [17]. It is hypothesized that a chronic disequilibrium and instability between the production and clearance of A in addition to its misfolding may lead, step by step, to synaptic alterations and glial activation [15]. The discovery of familial AD mutations in the APP gene [18] underlines the substantial role that APP integrity, trafficking, and metabolism may play in the wide spectrum of pathogenic potential factors in AD. However, the etiopathogenic mechanisms of the sporadic cases of the disease remain unknown in spite of constantly ongoing research. The deposition of A and the hyperphosphorylation of tau protein have been recognized as the main procedures that lead to the generation of neuritic plaques and neurofibrillary tangles, which are the principal pathognomonic postmortem diagnostic criteria of AD. A is derived from APP, a member of the nexins encoded on chromosome 21, which undergoes proteolysis by combined effects of - and ␥-secretases [19], resulting in the formation of 39 to 43 amino-acid peptides, which are deposited forming the basis of the neuritic plaques. In addition, oxidative stress is a dominant factor in the pathogenesis of AD [20], associated with morphological alterations of mitochondria, which are observed at any area of the brain including the cortex, the subcortical centers, and the cerebellar cortex [20–23]. It is well documented that morphological and functional alterations of mitochondria may also occur in a considerable number of degenerative disorders of the brain [24–29], associated frequently with oxidative stress [27, 30, 31] and vascular changes [31]. Morphological alterations of Golgi apparatus (GA) have been observed in nerve cells even in the initial stages of AD, when neurofibrillary tangles and neuritic plaques are still rare, seen mostly in the hippocampus and in a limited proportion of nerve cells in the
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MATERIAL AND METHODS
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The cortex of the vermis and the cerebellar hemispheres of twenty patients who suffered from AD, twelve men and eight women, aged 62–90 years, were studied in light and electron microscopy (Table 1). The patients fulfilled all the current neuropsychological, clinical, and laboratory diagnostic criteria of AD. The mean education of the patients was 16 years. They had sufficient fluency in speaking their native language. Two of the patients were bilingual. Screening procedures were applied, which included medical history, medical examination, cardiological investigation, physical neurologic assessment, psychiatric examination, and neuropsychological testing. Clinical and laboratory investigation of the patients included carotid duplex Doppler, computerized
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Braak and Braak stage
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The study of the cytoarchitecture of the cortex of the cerebellum, evaluation of dendritic arborization of neurons, morphometric estimation of dendritic branches, estimation of morphology, and density of dendritic spines were performed in light microscopy on thick sections stained according to rapid Golgi method (Fig. 1). For this reason, the remaining parts of the cerebellar cortex, after a long fixation in formalin, were processed for silver impregnation, according to rapid Golgi technique, which consisted of immersion of the tissue in potassium dichromate (7 g potassium dichromate in 300 mL water) for 10 days and post immersion in 1% silver nitrate for 10 days. Then the specimens
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tomography scanning, single-photon emission computed tomography, magnetic resonance imaging of the brain, and electroencephalography. Neuropsychological testing included Mini-Mental State Examination, Alzheimer’s Disease Assessment Scale-Cognitive Subscale, and Dementia Rating Scale [39]. The patients passed away from heart arrest; twelve of them had myocardial infarction one to nine months after the last clinical and laboratory evaluation. Eight of them were pronounced dead after sleep. The postmortem examination was performed soon after death within approximately 6 hours. In addition, we used ten brains apparently unremarkable, derived from healthy individuals of the same age range as the AD patients, who died accidentally, as normal controls.
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The thin sections were prepared in a Reichert Ultratome. Then the sections on the grids were contrasted with uranyl acetate and lead citrate, and the fine structure of the specimens was studied in a Zeiss electron microscope of the type 9aS. The study was particularly focused on the morphology of the organelles of the neurons, such as mitochondria, GA, endoplasmic reticulum, and endosomes. In addition, the study also focused on dendritic profiles, spines, axons, axonic collaterals, and synaptic components. The morphometric estimation at the level of electron microscopy was carried out on micrographs of a standard magnification of 56,000 X.
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Table 1 List of the AD brains included in the study. Thirty samples of each one of them from the vermis and the cerebellar hemispheres were studied in electron microscope from 1974 to 2011
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Samples of a small size (2 × 2 × 2 mm) were excised from various areas of the cortex of the vermis and the hemispheres of the cerebellum and immersed immediately in Sotelo’s fixing solution, which consisted of 1% paraformaldehyde, 2.5% glutaraldehyde in cacodylate buffer 0.1 M, adjusted at pH 7.35. Then all the specimens were postfixed by immersion in 1% osmium tetroxide for 30 min at 16◦ C and had undergone dehydration by immersion in graded alcohol solutions and propylene oxide.
Fig. 1. Purkinje cells (PC) from the uvula of the vermis of an AD case (Male 72 y). The limitation of the dendritic arborization is obvious. Golgi silver impregnation technique (Magnification = 1,200X, bar = 50 m).
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Statistical analysis
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RESULTS
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Electron microscopy is the most efficient method for observation, morphological and morphometric study, and evaluation of the organelles of the neuronal perikaryon, dendritic profiles, spines, synapses, neuron-glial relationships, and morphology of the capillaries in the brain in normal and pathological conditions. The study in electron microscopy revealed dilatation of the cisternae of the smooth endoplasmic reticulum and substantial fragmentation of the cisternae of GA in numerous Purkinje cells of the cerebellar cortex (Fig. 2). The cisternae of the GA were shorter in correlation to normal controls. Fragmentation of the cisternae of GA was also observed in granule cells in the vermis and the cerebellar hemispheres. It is worth emphasizing that the alterations of GA were also noticed in neurons without findings of tau pathology and in areas with minimal extracellular deposits
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Fig. 2. Purkinje cell from the inferior semilunar lobe of the cerebellar hemisphere of an AD case (Female 76 y). The dilatation of the cisternae of the GA and the alteration of the mitochondria are prominent in the perikaryon of the neuron. Electron micrograph (Magnification = 20,000X, bar = 0.2 m).
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Statistical evaluation was based on the Student’s ttest. 5,000 mitochondria and 600 GA were studied from 30 specimens of each one of the 20 AD brains and correlated with equal number of mitochondria and GA from 30 specimens of each one of the 10 normal controls. All the micrographs were studied and analyzed in the same way. Significance was taken as p < 0.05.
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underwent rapid dehydration by short immersion in graded alcohol solutions and embedded in paraffin. Thirty sections of each one of the specimens were prepared, at an alternative thickness of 100 m and 25 m. From each one of the specimens, thirty sections of 25 m were processed according to Golgi-Nissl technique by post-staining with methylene blue. In addition, samples were taken from hippocampus and temporal, frontal, parietal, and occipital lobes and were processed for Bodian staining, in order to obtain a global neuropathological estimation of AD lesions. After mounting in Permount, the sections were studied in a photomicroscope (Zeiss Axiolab). Neuropathological alterations were estimated and rated according to Braak and Braak staging [10, 40] and CERAD neuritic plaque score [41, 42]. The consensus recommendations concerning the neuropathological diagnosis of AD introduced by the National Institute on Aging and the Reagan Institute [43] were also respected.
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Fig. 3. Fragmentation of the cisternae of Golgi apparatus (GA), of a Purkinje cell from the uvula of the vermis of an AD case (Male 72 y). Electron micrograph (Magnification = 128,000X, bar = 0.1 m).
of A (Fig. 3). The number of the vacuoles and vesicles, which are associated with the Golgi complex, was reduced in most Purkinje and granule cells of the cerebellum. Since vacuolization of the cell body was not
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noticed in the majority of neurons, we may hypothesize that the alterations of the GA may occur quite independently from the cytoplasmic vacuolization. It has to be underlined that alterations of GA were also observed in the soma of astrocytes (Fig. 4) and in endothelial cells as well as in the pericytes of patients suffering from AD. Mitochondrial pathology was observed in the soma and dendrites and in a large number of spines of dendritic branches in all of the studied specimens (Fig. 5). Pathological findings consisted of (a) a considerable change of the shape and size of mitochondria, (b) fragmentation of mitochondrial cristae and (c) accumulation of osmiophilic material in a substantial number of mitochondria. In many dendritic branches, mitochondria showed unusual polymorphism, such as concentric arrangement of the cristae or arrangement of cristae according to the major diameter of the organelle. In numerous climbing fibers, mitochondria were seen as very elongated and packed together in large numbers. Many round mitochondria of a short diameter were intermixed with dense bodies. Morphological alterations of mitochondria coexisted with the changes of the shape and size of the cisternae of the GA and the alterations of microtubules, which were roughly dispersed in the perykarion and dendritic profiles of Purkinje cells in AD brains (Fig. 6). Morphometric estimation of Purkinje cell mitochondria in normal control brains revealed that long ellipsoid mitochondria in the spines have an average diameter of 650 ± 250 nm and a mean axial ratio of 1.9 ± 0.2 (p < 0.005), whereas small round mitochondria
Fig. 5. Dendritic profile of a Purkinje cell in the molecular layer of the nodule in an AD case (Male 78 y). Numerous twisted microtubules (MT) are seen intermixed with abnormal mitochondria. Abnormal synaptic profiles (S) are seen on the surface of the dendritic branch. Electron micrograph (Magnification = 28,000X, bar = 0.3 m).
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Fig. 4. Fragmentation of the cisternae of Golgi apparatus (GA), abnormal mitochondria (M), dense bodies (DB), and lysosomes in a Bergmann’s glial cell of the superior semilunar lobe of the cerebellum of an AD case (Male 80 y). Electron micrograph (Magnification = 36, 000X, bar = 0.3 m).
Fig. 6. Small round mitochondria (M), dense bodies, and atypically dispersed microtubules and endocytotic vesicles (EV) are seen in the perikaryon of Purkinje cell of the nodule in an AD case (Male 82 y). Electron micrograph (Magnification = 128,000X bar = 0.03 m).
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Fig. 8. A mossy fiber (MF) terminal in the granule layer of the superior semilunar lobe of the cerebellum in an AD case (Female 85 y). The electron microscope reveals a marked polymorphism and pleomorphism of the dramatically decreased synaptic vesicles and the presence of multivesicular body (MVB). Electron micrograph (Magnification = 200,000X, bar = 0.02 m).
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have a mean radius of 350 nm. The mean diameter of ellipsoid mitochondria in AD brains was estimated at 480 ± 250 nm (p < 0.005) and the mean axial ratio was 1.7 ± 0.2 nm (p < 0.005). The small global mitochondria appear to have a mean radius of 280 nm. Many polymorphic endocytotic vesicles were also observed in Purkinje cells and granule cells, and in endothelial cells and pericytes of the capillaries of the cerebellar cortex. Thick perivascular astrocytic processes were seen including numerous large pinocytotic vesicles. In addition, electron microscopy revealed morphological alterations of spines and a considerable decrease in spine density, mostly concerning secondary and tertiary Purkinje cell dendritic branches (Fig. 7). Many spines contained large multivesicular bodies, abnormal polymorphic mitochondria, and atypical spine apparatus. Many abnormal giant spines emerged from terminal Purkinje cell dendritic branches. Several presynaptic terminals of parallel and mossy fibers in the cerebellum of AD brains were characterized by polymorphism and pleomorphism of the limited synaptic vesicles (Fig. 8). Astrocytic proliferation was also prominent both in the vermis and the cerebellar hemispheres, also demonstrating abnormal elongated mitochondria and fragmented cisternae of GA.
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Fig. 7. Synaptic profile between parallel fiber (PF) and Purkinje cell dendritc spine (DS) in the molecular layer of the superior semilunar lobe of the cerebellum in an AD case (Male 82 y). Poverty and pleomorphism of synaptic vesicles (sv) is obvious. Electron micrograph (Magnification = 167,000X, bar = 0.04 m).
DISCUSSION Protein trafficking is a continuous process in neurons either in normal or in pathological conditions. Any abnormal modification or deviation of protein trafficking may be crucial in inducing a stream of phenomena which may lead to serious disorders. APP is a ubiquitous Type 1 membrane glycoprotein, which is continuously trafficking in nerve cells [44], soma, and dendrites and along central and peripheral axons in an anterograde way. APP, during its trafficking to the cell surface and in the endocytic pathway, generates A, ranging in size from 37 to 43 amino acids, by cleavage of the APP C terminal fragment. APP, on the other hand, undergoes sequential cleavages by two intramembranous proteases, namely -secretase (BACE-1), which has its active site in the lumen [45], and ␥-secretase, which contains presenilin (PS), nicastrin, Aph-1, and the Pen-2 [46] proteins. Amyloidogenic activity may also occur in the endocytic pathway of APP [36], since BACE-1 localizes to the Golgi and endosomes, expressing the highest activity in the endosomal compartments [47]. In addition, APP undergoes secretory cleavages by metalloproteases [48]. The generated soluble oligomers of A
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neuronal interactions, is also related to down regulation of APP, which results in increased endocytosis of nerve growth factor and nerve growth factor receptors [75]. However BACE1, which is responsible for -secretase cleavage of APP, trafficking in neuronal recycling endosomes [76] might be related to presynaptic production of A, being reasonably involved in the pathogenic mechanism of AD [77]. It is also known that A may increase the production of reactive oxygen species [78] in the mitochondria, which in turn may seriously affect mitochondrial function [79], a fact which may further induce synaptic degeneration in AD [80], since many dendritic branches and abnormal spines were seen including unusual polymorphic mitochondria [23]. Morphological alterations of mitochondria are associated with a decrease of mitochondrial energy production, which in turn increases APP amyloidogenic activity [81] and induces synaptic degeneration [82] and a substantial decrease of spine density in the dendritic profiles [23]. DISCLOSURE STATEMENT The author’s disclosure is available online (http:// www.j-alz.com/disclosures/view.php?id=2285).
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are considered as substantial etiological component in the pathogenesis of AD [49]. GA may have a substantial contribution in the trafficking of APP and the amyloidogenic process. The morphological changes of GA, which are noticed even in the initial stages of AD, plead in favor of the hypothesis that impairment of trafficking in Golgi cisternae and the endosomes may be crucial factors in amyloidogenesis. In addition, the low density lipoprotein receptor-related protein (LRP), which is cleaved by furin inside the trans-Golgi network, may play a substantial role in mediating ligand internalization [50, 51], since many ligands may bind LRP [52]. Additionally, PS1, which is a component of ␥-secretase, is mainly located in the endoplasmic reticulum, cisternae of GA [53], and synapses, where it associates with the cadherin/catenin adhesion complex [54]. In familial cases of AD, mutations in PS1 induce a substantial increase in the formation of A42 , contributing decisively in the pathogenic process of the disease [55]. It is worth to mention that PS1 is associated with cytoskeleton [56] and also may play a role in the trafficking of N-cadherin to the plasma membrane [57], a procedure which is crucial for synaptic activity, since N-cadherin is localized at the synapses, providing an adhesive force across the synaptic cleft [58, 59]. In addition, the overexpression of PS1 may result in decreasing sialysation of the cell surface protein NCAM, which has been implicated, among the others, in synaptic plasticity and axonal outgrowth [60]. At the same time, mutant forms of the PS1 protein may alter glycoprotein processing [61] as well as lysosomal proteolysis and autophagy [62]. Alterations of GA may have an essential effect in protein glycosylation, since the trans-Golgi network is associated with the catalysis of soluble glycoproteins [63, 64]. In fact, glycosylation of proteins is among the major processing activities of the GA, which occurs through a large number of sequential steps, each requiring its own enzymes [65]. It is also well established by immunocytochemical and morphometric studies in amyotrophic lateral sclerosis, AD, and aging, that GA is a reliable index of activity or degeneration and aging [32, 66–69]. The fragmentation of GA may also affect dendritic protein trafficking, which plays a very important role in dendritic remodeling or arbor stability, since microtubules and microtubule associated proteins are closely associated with Golgi outpost and trafficking of vesicles and proteins to terminal dendritic branches and spines [70–74]. The plasticity of the dendrites, axons, and synapses, which is an essential procedure for remodeling of
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