Journal of ISSN: 2373-6410JNSK

Neurology & Stroke
Editorial
Volume 2 Issue 3 - 2015
Golgi apparatus in Alzheimer’s disease
Stavros J Baloyannis*
Research Institute for Alzheimer’s disease, Aristotelian University, Greece
Received: June 17, 2014| Published: June 19, 2015
*Corresponding author: Stavros J Baloyannis, MD, PhD, Professor Emeritus, Aristotelia Univesity, Angelaki 5, Thessaloniki 54621, Greece. Tel: +302310270434; Fax: +302310270434; E-mail: @
Citation: Baloyannis SJ (2015) Golgi apparatus in Alzheimer’s disease. J Neurol Stroke 2(3): 00056. DOI: 10.15406/jnsk.2015.02.00056 DOI: 10.15406/jnsk.2015.02.00056

Keywords: Alzheimer’s disease; Golgi apparatus; Organelles; Electron microscopy; Morphometry; Protein trafficking; Aβ peptide; Synaptic plasticity

Abbreviations

AD: Alzheimer’s Disease; GA: Golgi Apparatus; ER: Endoplasmic Reticulum; mDNA: mitochondrial DNA; CytOX: Cytochrome c Oxidase; PS1: Preseniline1; ROS: Reactive Oxygen Species; APP: Amyloid Precursor Protein; AβPP: Amyloid-β Precursor Protein; cdk5: cyclin-dependent kinase-5; UPR: adaptive mechanisms of the Unfolded Protein Response

Editorial

Alzheimer’s disease (AD) is the most common cause of progressive and irreversiblepresenile and senile dementia of unavoidable tragicoutcome, affecting millions of humansworldwide. Even from the last decades of the 20th century AD has become a seriousmedical challenge for aging population, inducing many ethical, legal, social, humanitarian, philosophical [1] and economic problems without an obvious perspective clarityfor the near future, despite the quotidian ongoing research [2].

The clinical phenomena of the disease are characterized by profound memory loss, visuo-spatial disorientation, loss of professional skills, learning inability, decline of speech fluency,gradual dysarthria,mood and behavioral disturbances and personality changes,phenomena which appear increasingly as the disease advances, complimented frequently by autonomic disorders andepileptic seizures, which progressively result in a final vegetative state, which is the common darkepilogue of the tragic life of the patients.

The neuropathological profile of AD is plotted many years prior to phenomenological appearance of the disease. It consists of (a) abnormal accumulation of Aβ peptide in the form of neuritic plaques or diffusely dispersed in the neuropile and (b) intracellular accumulations of hyper-phosphorylated tau protein in the form of neurofibrillary tangles and (c) selective neuronal loss. All these findings, which compose the main neuropathological diagnostic criteria, as key hallmarks of AD [3,4] are usually observed, been dispersed in the hippocampus, the cortex of the cerebral hemispheres, and in many subcortical neuronal networks, which play a substantial role in cognition.

Electron microscopy enlarged the horizons of morphological investigation in AD and revealed dendritic, spine andmarked synaptic pathology, in association with substantialorganelle alterations, involving mostly microtubules, mitochondria [5,6], Golgi apparatus (GA) [7] and endoplasmic reticulum (ER) [8] clearly observed even in areas of the brain, where dendritic plaques and neurofibrillary tangles are infrequent.

The alterations of ER and GA result inaccumulation of misfolded proteins and neuronal loss [9], given that failure of the adaptive mechanisms of the unfolded protein response (UPR) may result in chronic accumulation of misfolded proteins in the ER [10] and impaired amyloid precursor protein (APP) processing and trafficking [11].

In addition Tau protein, which is accumulated in ER, Golgi complexes, and mitochondria [12], may activate the unfolded protein response by impairing ER-associated degradation [13]. In addition all newly synthesized proteins, which are used for membranic processes, insertion or secretion, axoplasmic or dendritic flow and synaptic activity, including APP, are practically processed through the vesicles and the cisternae of Golgi complex [14].

Trafficking from the cell surface and proper sorting of APP and its cleaving involved enzymes require an intact and proper functioning Golgi complex [15]. APP, during its trafficking,in the GAand in the endocytic pathway, generates Aβ peptide, ranging in size from 37 to 43 amino acids, by cleavage of the APP C terminal fragment [16]. PS1, which is a component of γ-secretase and selectively increase the secretion of the Aβ (1-42) peptide, is mainly located in the ER and the cisternae of GA [17], trafficking to synapses, where it becomes component of synaptic and endothelial adherent junctions [18].

The GA in the majority of the early cases of AD is fragmented and atrophic in comparison with age matched normal controls [19]. The number of the vacuoles and vesicles, which are associated with the Golgi complex, are reduced in most of the Purkinje and granule cells of the cerebellum, the hippocampal neurons, the acoustic and visual cortices as well as the hypothalamus [20]. It must be emphasized that alterations of GA are also observed in the astrocytes, in endothelial cells as well as in pericytes in AD brains [21].
The normal structure of the cisternae and vesicles of the GA in the cell body is maintained by the proteins of the Golgi matrix [22]. It is reasonable that alteration of these structural proteins as an early phenomenon in AD may induce GA fragmentation and atrophy [23]. The accumulation of Aβ peptide in AD, at the subclinical period, may cause fragmentation of GA by phosphorylation of GM130 or GRASP65 (Golgi reassembly and stacking protein of 65 kD) [24,25] proteins by the activation of cyclin-dependent kinase-5 (cdk5), as it is well documented in transgenic mouse models [26].

In addition alterations of GA may influence protein glycosylation [27], which is among the major processing activities of the trans-Golgi network, occurring through numerous sequential steps, each of them requiring its own enzymes [28].

In the pathogenic chain of AD, the further fragmentation of GA induced by Aβ peptideoverproduction [29] may reasonably affect dendritic protein trafficking, which is essentialfor dendritic remodeling and arbor stability, since microtubules are closely associated with Golgi outpost and trafficking of vesicles and proteins towards the terminal dendritic branches and spines [30]. At the same time the Aβ peptide which is accumulated in multivesicular bodies [31], in association with mitochondrial dysfunction [32] may inducedisruption of the synapses [31], a fact which is closely related with the cognitive decline in AD.

The morphological alterations of GA, which are observed even at the initial stages of AD, plead in favor of the hypothesis that impairment of trafficking in Golgi cisternae and endosomes and ER stress may be one of the crucial factors in amyloidogenesis [27,33].

It is an undoubted ascertainment that there is no effective therapeutic intervention in AD for the time being. The majority of the current therapeutic attempts have temporal effects and induce symptomatic alleviation only.

A therapeutic philosophy aiming at protection from oxidative stress, mitochondrial damage [32] and hypoxic perturbations on one hand and protection of the endoplasmic reticulum [8] and Golgi complex from stress and fragmentation [34] on the other hand, may be beneficial in the initial stages of AD, promoting restoration and remodeling of dendrites [30], regeneration of spines, synaptogenesis and synaptic plasticity.

References

  1. Baloyannis S (2010) The philosophy of dementia. Encephalos 47(3): 109-130.
  2. World Health Organization (WHO) (2012) Dementia: a public healthpriority. World Health Organization, Geneva, pp. 112.
  3. Alzheimer's Association (2014) 2014 Alzheimer's disease facts and figures. Alzheimers Dement 10(2): e47-e92.
  4. Ballatore C, Lee VM, Trojanowski JQ (2007) Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci 8(9): 663-672.
  5. Baloyannis SJ, Manolides SL, Manolides LS (2011) Dendritic and spinal pathology in the acoustic cortex in Alzheimer's disease: morphological estimation in Golgi technique and electron microscopy. Acta Otolaryngol 131(6): 610-612.
  6. Baloyannis SJ (2013) Alterations of mitochondria and golgi apparatus are related to synaptic pathology in Alzheimer's disease. In: Kishore U (Ed.), Neurodegenerative Diseases. InTech, Rijeka, Croatia, pp. 101-123.
  7. Baloyannis S (2002) The Golgi apparatus of Purkinje cells in Alzheimer's disease. In: BohlJ (Ed.), Neuropathology Back to the Roots. Shaker Vertag, Aachen, Germany, pp. 1-10.
  8. Hetz C, Mollereau B (2014) Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases. Nat Rev Neurosci 15(4): 233-249.
  9. Hoozemans JJ, van Haastert ES, Nijholt DA, Rozemuller AJ, Eikelenboom P, et al. (2009) The unfolded protein response is activated in pretangle neurons in Alzheimer's disease hippocampus. Am J Pathol 174(4): 1241-1251.
  10. Placido AI, Pereira CM, Duarte AI, Candeias E, Correia SC, et al. (2015) Modulation of endoplasmic reticulum stress: an opportunity to prevent neurodegeneration? CNS Neurol Disord Drug Targets 14(4): 518-533.
  11. Placido AI, Pereira CM, Duarte AI, Candeias E, Correia SC, et al. (2014) The role of endoplasmic reticulum in amyloid precursor protein processing and trafficking: Implication's for Alzheimer's disease. Biochim Biophys Acta 1842(9): 1444-1453.
  12. Tang Z, Ioja E, Bereczki E, Hultenby K, Li C, et al. (2025) mTor mediates tau localization and secretion: Implication for Alzheimer's disease. Biochim Biophys Acta 1853(7): 1646-1657.
  13. Abisambra JF, Jinwal UK, Blair LJ, O'Leary JC, Li Q, et al. (2013) Tau accumulation activates the unfolded protein response by impairing endoplasmic reticulum-associated degradation. J Neurosci 33(22): 9498-9507.
  14. Thinakaran G, Koo EH (2008) Amyloid precursor protein trafficking, processing, and function. J BiolChem 283(44): 29615-29619.
  15. Choy RW, Cheng Z, Schekman R (2012) Amyloid precursor protein (APP) traffics from the cell surface via endosomes for amyloid β (Aβ) production in the trans-Golgi network. Proc Natl Acad Sci U S A 109(30): E2077-E2082.
  16. Prabhu Y, Burgos PV, Schindler C, Farias GG, Magadan JG, et al. (2012) Adaptor protein 2-mediated endocytosis of the β-secretase BACE1 is dispensable for amyloid precursor protein processing. Mol Biol Cell 23(12): 2339-2351.
  17. Annaert WG, Levesque L, Craessaerts K, Dierinck I, Snellings G, et al. (1999) Presenilin 1 controls gamma-secretase processing of amyloid precursor protein in pre-Golgi compartments of hippocampal neurons. J Cell Biol 147(2): 277-294.
  18. Georgakopoulos A, Marambaud P, Friedrich VL, Shioi J, Efthimiopoulos S, et al. (2000) Presenilin-1: a component of synaptic and endothelial adherens junctions. Ann NY Acad Sci 920: 209-214.
  19. Stieber A, Mourelatos Z, Gonatas NK (1996) In Alzheimer’s disease the Golgi apparatus of a population of neurons without neurofibrillary tangles is fragmented and atrophic. Am J Pathol 148(2): 415-426.
  20. Baloyannis SJ, Mavroudis I, Mitilineos D, Baloyannis IS, Costa VG (2014) The hypothalamus in Alzheimer's disease: a golgi and electron microscope study. Am J Alzheimers Dis Other Demen pii: 1533317514556876.
  21. Baloyannis SJ (2014) Golgi apparatus and protein trafficking in Alzheimer's disease. J Alzheimers Dis 42(Suppl 3): S153-S162.
  22. Xiang Y, Wang Y (2011) New components of the Golgi matrix. Cell Tissue Res 344(3): 365-379.
  23. Sun KH, de Pablo Y, Vincent F, Johnson EO, Chavers AK, et al. (2008) Novel genetic tools reveal Cdk5’s major role in Golgi fragmentation in Alzheimer’s disease. Mol Biol Cell 19(7): 3052-3069.
  24. Barr FA, Puype M, Vandekerckhove J, Warren G (1997) GRASP65, a protein involved in the stacking of Golgi cisternae. Cell 91(2): 253-262.
  25. Barr FA, Nakamura N, Warren G (1998) Mapping the interaction between GRASP65 and GM130, components of a protein complex involved in the stacking of Golgi cisternae. EMBO J 17(12): 3258-3268.
  26. Lane JD, Lucocq J, Pryde J, Barr FA, Woodman PG, Allan VJ, Lowe M (2002) Caspase-mediated cleavage of the stacking protein GRASP65 isrequired for Golgi fragmentation during apoptosis. J Cell Biol 156(3): 495-509.
  27. Schedin-Weiss S, Winblad B, Tjernberg LO (2014) The role of protein glycosylation in Alzheimer disease. FEBS J 281(1): 46-62.
  28. McFarlane I, Georgopoulou N, Coughlan CM, Gillian AM, Breen KC (1999) The role of the protein glycosylation state in the control of cellular transport of the amyloid β precursor protein. Neuroscience 90(1): 15-25.
  29. Joshi G, Chi Y, Huang Z, Wang Y (2014) Aβ-induced Golgi fragmentation in Alzheimer's disease enhances Aβ production. Proc Natl Acad Sci U S A 111(13): E1230-E1239.
  30. Szebenyi G, Bollati F, Bisbal M, Sheridan S, Faas L, et al. (2005) Activity-driven dendritic remodeling requires microtubule associated protein 1A. Curr Biol 15(20): 1820-1826.
  31. Takahashi RH, Milner TA, Li F, Nam EE, Edgar MA, et al. (2002) Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am J Pathol 161(5): 1869-1879.
  32. Baloyannis SJ (2014) Mitochondria and Alzheimer’s Disease. J Neurol Stroke 1(5): 00028.
  33. Kudo T, Okumura M, Imaizumi K, Araki W, Morihara T, et al. (2006) Altered localization of amyloid precursor protein under endoplasmic reticulum stress. Biochem Biophys Res Commun 344(2): 525-530.
  34. Sundaram JR, Poore CP, Sulaimee NH, Pareek T, Asad AB, et al. (2013) Specific inhibition of p25/Cdk5 activity by the Cdk5 inhibitory peptide reduces neurodegeneration in vivo. J Neurosci 33(1): 334-343.
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