The Fundamental Role of Neuroinflammation at the Beginning and Progression of Alzheimer’s Disease


  • Yousef Sawikr Pharmacology and Toxicology Department, Medicine Faculty, Ajdabiya University, Libya.



Alzheimer disease, S100B, cytokines, RAGE.


The majority of astrocytes are responsible for the expression and release of S100B, a 21-kDa calcium-binding protein of the EFhand type (helix E-loop-helix F). It is mostly present in the neurological system and, depending on concentration, has different (beneficial, detrimental) effects on neurons, astrocytes, and microglia. an effect on the survival and development of both glia and neuronal cells. Patients with Down Syndrome and Alzheimer's Disease (AD) have brains that are overexpressed with the S100 protein Down Syndrome (DS). Increased S100B concentrations are linked to brain trauma and ischemia, most likely due to astrocyte destruction. As S100B appears to influence multiple neuropathological mechanisms in (AD) , a pivotal role for S100B as a significant contributor to (AD) pathology has emerged.

Studies of S100B overexpression, S100B localization, multiple relationships between S100B and increase amyloid precursor protein, the interaction between S100B and dystrophic neuritis plaques, and change in a neurofibrillary tangle in Alzheimer's disease focus on providing evidence for the involvement of S100B in Alzheimer's disease pathology and neuronal loss. The significance of S100B in head trauma and degenerative brain disease is the central subject of this review. Overexpressing s100B, which also causes more astrogliosis and microgliosis, speeds up the pathogenesis of Alzheimer's disease. Numerous clinical problems have been associated with an increase in S100B, a neurotropic signaling protein.


Wyss-Coray T and Rogers J (2012) “Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature.,” Cold Spring Harb. Perspect. Med., vol. 2, no. 1, p. a006346.

Xiao Q, Yan P, Ma X, Liu H, Perez R, Zhu A, Gonzales E, Burchett J, Schuler D, Cirrito J, Diwan A, and Lee J (2014) “Enhancing Astrocytic Lysosome Biogenesis Facilitates A Clearance and Attenuates Amyloid Plaque Pathogenesis,” J. Neurosci., vol. 34, no. 29, pp. 9607–9620

Sidoryk-Wegrzynowicz M, Wegrzynowicz M, Lee E, Bowman A, and Aschner M (2011) “Role of astrocytes in brain function and disease.,” Toxicol. Pathol., vol. 39, no. 1, pp. 115–23,

D’Andrea M, Cole G, Ard M (2004) “The microglial phagocytic role with specific plaque types in the Alzheimer disease brain.,” Neurobiol. Aging, vol. 25, no. 5, pp. 675–83.

Sidoryk-Wegrzynowicz M and Aschner M (2013) “Role of astrocytes in manganese mediated neurotoxicity.,” BMC Pharmacol. Toxicol., vol. 14, p. 23.

Vesce S, Rossi D, Brambilla L, Volterra A (2007) “Glutamate release from astrocytes in physiological conditions and in neurodegenerative disorders characterized by neuroinflammation,”Int Rev Neurobiol.2007;82:57-71.doi: 10.1016/S0074-7742(07)82003-4.

Allen, P. M., Murphy, K. M., Schreiber, R. D., & Unanue, E. R. (1999). Immunology at 2000. Immunity, 11(6), 649-651

Fung A, Vizcaychipi M, Lloyd D, Wan Y, and Ma D (2012) “Central nervous system inflammation in disease related conditions: mechanistic prospects.,” Brain Res., vol. 1446, pp. 144–55.

Boulanger L, Huh G, and Shatz C (2001) “Neuronal plasticity and cellular immunity: shared molecular mechanisms.,” Curr. Opin. Neurobiol., vol. 11, no. 5, pp. 568–78.

Joseph, J. A., Shukitt-Hale, B., Casadesus, G. E. M. M. A., & Fisher, D. (2005). Oxidative stress and inflammation in brain aging: nutritional considerations. Neurochemical research, 30(6), 927-935.

Campbell A (2004) “Inflammation, neurodegenerative diseases, and environmental exposures.,” Ann. N. Y. Acad. Sci., vol. 1035, pp. 117–32.

Nadeau S and Rivest S (2003) “Glucocorticoids play a fundamental role in protecting the brain during innate immune response‏,” J. Neurosci. 2; 23(13): 5536–5544.doi: 10.1523/JNEUROSCI.23-13-05536.2003

Huell M, Strauss S, Volk B, Berger M, Bauer J (1995) “Interleukin-6 is present in early stages of plaque formation and is restricted to the brains of Alzheimer’s disease patients,” Acta Neuropathol., vol. 89, no. 6, pp. 544–551.

Sindic C, Chalon M, Cambiaso C, Laterre E, Masson P (1982) “Assessment of damage to the central nervous system by determination of S-100 protein in the cerebrospinal fluid.,” J. Neurol. Neurosurg. Psychiatry, vol. 45, no. 12, pp. 1130–1135.

Mata M, Alessi D, Fink D (1990) “S100 is preferentially distributed in myelin-forming Schwann cells,” J. Neurocytol., vol. 19, no. 3, pp. 432–442.

Zimmer D, Cornwall E, Landar A, Song W (1995) “The S100 protein family: History, function, and expression,” Brain Res. Bull., vol. 37, no. 4, pp. 417–429.

Donato R (1999) “Functional roles of S100 proteins, calcium-binding proteins of the EF-hand type,” Biochim. Biophys. Acta - Mol. Cell Res., vol. 1450, no. 3, pp. 191–231.

Ichikawa H, Jacobowitz D, Sugimoto T (1997) “S100 protein-immunoreactive primary sensory neurons in the trigeminal and dorsal root ganglia of the rat‏,” Brain Res. 14;748(1-2):253-7.doi: 10.1016/s0006-8993(96)01364-9.

Yang Q, A. Hamberger, Hyden H, Wang S, Stigbrand T, Haglid K (1995) “S-100β has a neuronal localisation in the rat hindbrain revealed by an antigen retrieval method,” Brain Res., vol. 696, no. 1–2, pp. 49–61.

Peskind E, Griffin W, Akama K, Raskind M,Van Eldik L (2001) “Cerebrospinal fluid S100B is elevated in the earlier stages of Alzheimer’s disease,” Neurochem. Int., vol. 39, no. 5–6, pp. 409–413.

Mrak R and Griffin W (2005) “Glia and their cytokines in progression of neurodegeneration.,” Neurobiol. Aging, vol. 26, no. 3, pp. 349–54.

Cairns N, Chadwick A, Luthert P, Lantos P (1992) “Astrocytosis, βA4-protein deposition and paired helical filament formation in Alzheimer’s disease,” J. Neurol. Sci., vol. 112, no. 1–2, pp. 68–75.

Zhang X and Song W (2013) “The role of APP and BACE1 trafficking in APP processing and amyloid-β generation.,” Alzheimers. Res. Ther., vol. 5, no. 5, p. 46.

Selkoe D (2001) “Alzheimer’s disease: genes, proteins, and therapy.,” Physiol. Rev., vol. 81, no. 2, pp. 741–66,

Van Eldik L and Zimmer D (1987) “Secretion of S-100 from rat C6 glioma cells,” Brain Res., vol. 436, no. 2, pp. 367–370.

Gerlach R , Demel G, König H, Gross U, Prehn J, Raabe A, Seifert V, Kögel D (2006)“Active secretion of S100B from astrocytes during metabolic stress.,” Neuroscience, vol. 141, no. 4, pp. 1697–701.

Ciccarelli R, Di Iorio P, Bruno V, Battaglia G, D'Alimonte I, D'Onofrio M, Nicoletti F, Caciagli F (1999) Activation of A(1) adenosine or mGlu3 metabotropic glutamate receptors enhances the release of nerve growth factor and S-100beta protein from cultured astrocyte. Glia Sep;27(3):275-81

Whitaker-Azmitia P, Murphy R, Azmitia E (1990) “Stimulation of astroglial 5-HT1A receptors releases the serotonergic growth factor, protein S-100, and alters astroglial morphology.,” Brain Res., vol. 528, no. 1, pp. 155–8.

Edwards M and Robinson, S (2006) “TNF alpha affects the expression of GFAP and S100B: implications for Alzheimer’s disease.,” J. Neural Transm., vol. 113, no. 11, pp. 1709–15..

Souza D, Leite M, Quincozes-Santos A, Nardin P, Tortorelli L, Rigo M, C. Gottfried C, Leal R, Gonçalves C (2009) “S100B secretion is stimulated by IL-1beta in glial cultures and hippocampal slices of rats: Likely involvement of MAPK pathway.,” J. Neuroimmunol., vol. 206, no. 1–2, pp. 52–7.

Peña L, C. Brecher, and Marshak D (1995) “β-amyloid regulates gene expression of glial trophic substance S100β in C6 glioma and primary astrocyte cultures‏,” Mol. brain Res. 1;34(1):118-26.doi:10.1016/0169 328x(95)00145-i.

Iuvone T, Esposito G, De Filippis D, Bisogno T, Petrosino S, Scuderi C, Di Marzo V, Steardo L (2007) “Cannabinoid CB1 receptor stimulation affords neuroprotection in MPTP-induced neurotoxicity by attenuating S100B up-regulation in vitro.,” J. Mol. Med. (Berl)., vol. 85, no. 12, pp. 1379–92.

Pinto S, Gottfried C, Mendez A, Gonçalves D, Karl J, Gonçalves C, Wofchuk S, Rodnight R (2000) “Immunocontent and secretion of S100B in astrocyte cultures from different brain regions in relation to morphology.,” FEBS Lett., vol. 486, no. 3, pp. 203–7.

Gery I and WaksmanB (1972) “Potentiation of the T-lymphocyte response to mitogens II. The cellular source of potentiating mediator (s),” J. Exp. Med., vol. 136, no. 1, pp. 143–155.

Sharma V, (2011) “Neuroinflammation in Alzheimer’s disease and Involvement of Interleukin-1: A Mechanistic View,” Int. J. Pharm. Sci.

Zilka N, Ferencik M, Hulin I (2006) “Neuroinflammation in Alzheimer ’ s disease : protector or promoter ?,” vol. 107, no. 2, pp. 374–383..

Klegeris A and McGeer P (2005) “Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Other Anti- Inflammatory Agents in the Treatment of Neurodegenerative Disease,” Curr. Alzheimer Res., vol. 2, no. 3, pp. 355–365.

Lee S, Liu W, Dickson D, Brosnan C, Berman J (1993) “Cytokine production by human fetal microglia and astrocytes. Differential induction by lipopolysaccharide and IL-1 beta.,” J. Immunol., vol. 150, no. 7, pp. 2659–67.

GE Y and LAHIRI D (2002) “Regulation of Promoter Activity of the APP Gene by Cytokines and Growth Factors,” Ann. N. Y. Acad. Sci., vol. 973, no. 1, pp. 463–467.

Shaftel S, Griffin W, O’Banion M (2008) “The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective.,” J. Neuroinflammation, vol. 5, p. 7.

Giulian D, Woodward J, Young D, Krebs J, Lachman L (1988) “Interleukin-1 injected into mammalian brain stimulates astrogliosis and neovascularization.,” J. Neurosci., vol. 8, no. 7, pp. 2485–90.

Sheng j, Ito K, Skinner R, Mrak R, Rovnaghi C, Van Eldik L, Griffin W (1996) “In vivo and in vitro evidence supporting a role for the inflammatory cytokine interleukin-1 as a driving force in Alzheimer pathogenesis.,” Neurobiol. Aging, vol. 17, no. 5, pp. 761–6.

Griffin W, Sheng J, Roberts G, Mrak R (1995) “Interleukin-1 expression in different plaque types in Alzheimer’s disease: significance in plaque evolution.,” J. Neuropathol. Exp. Neurol., vol. 54, no. 2, pp. 276–81.

Mackenzie I, Hao C, Munoz D (1995) “Role of microglia in senile plaque formation,” Neurobiol. Aging, vol. 16, no. 5, pp. 797–804.

Griffin W and Mrak R (2002) “Interleukin-1 in the genesis and progression of and risk for development of neuronal degeneration in Alzheimer’s disease.,” J. Leukoc. Biol., vol. 72, no. 2, pp. 233–8.

Mrak R and Griffin W (2000) “Interleukin-1 and the immunogenetics of Alzheimer disease.,” J. Neuropathol. Exp. Neurol. vol. 59, no. 6, pp.471–6.

Mrak R (2001) “The role of activated astrocytes and of the neurotrophic cytokine S100B in the pathogenesis of Alzheimer’s disease,” Neurobiol. Aging, vol. 22, no. 6, pp. 915–922..

Hu J and Van Eldik L (1999) “Glial-derived proteins activate cultured astrocytes and enhance beta amyloid-induced glial activation,” Brain Res., vol. 842, no. 1, pp. 46–54, Sep. 1999.

Monnier V and Cerami A (1981) “Nonenzymatic browning in vivo: possible process for aging of long-lived proteins,” Science (80-. )., vol. 211, no. 4481, pp. 491–493.

Ma L and Nicholson L (2004) “Expression of the receptor for advanced glycation end products in Huntington’s disease caudate nucleus,” Brain Res., vol. 1018, no. 1, pp. 10–17.

Brett J, Schmidt A, Yan S, Zou Y, Weidman E, Pinsky D, Nowygrod R, Neeper M, Przysiecki C, Shaw A (1993) “Survey of the distribution of a newly characterized receptor for advanced glycation end products in tissues.,” Am. J. Pathol., vol. 143, no. 6, pp. 1699–712.

Takeda S, Sato N, Morishita R (2014) “Systemic inflammation, blood-brain barrier vulnerability and cognitive/non-cognitive symptoms in Alzheimer disease: relevance to pathogenesis and therapy.,” Front. Aging Neurosci., vol. 6, p. 171.

Onyango I, Tuttle J, Bennett J (2005) “Altered intracellular signaling and reduced viability of Alzheimer’s disease neuronal cybrids is reproduced by beta-amyloid peptide acting through receptor for advanced glycation end products (RAGE).,” Mol. Cell. Neurosci., vol. 29, no. 2, pp. 333–43,

Guglielmotto M, Giliberto L, Tamagno E, and Tabaton , “Oxidative stress mediates the pathogenic effect of different Alzheimer’s disease risk factors.,” Front. Aging Neurosci., vol. 2, p. 3, Jan. 2010.

Schmidt B, Braun H, Narlawar R, (2005) “Drug development and PET-diagnostics for Alzheimer’s disease.,” Curr. Med. Chem., vol. 12, no. 14, pp. 1677–95.

Sasaki N, Toki S, Chowei H, Saito T (2001) “Immunohistochemical distribution of the receptor for advanced glycation end products in neurons and astrocytes in Alzheimer’s disease‏,” Brain Res.

Adami C, Bianchi R, Pula G, Donato R (2004) “S100B-stimulated NO production by BV-2 microglia is independent of RAGE transducing activity but dependent on RAGE extracellular domain.,” Biochim. Biophys. Acta, vol. 1742, no. 1–3, pp. 169–77.




How to Cite

Sawikr, Y. (2022). The Fundamental Role of Neuroinflammation at the Beginning and Progression of Alzheimer’s Disease. Scientific Journal for Faculty of Science-Sirte University, 2(2), 91–98.