The involvement of the brain microenvironment in Alzheimer’s Disease
AbstractThe recent decision by some “pharma company” to abandon the research in the field of Alzheimer’s Disease should not scare the patients and their familial: many other companies and research institutes are strongly working with the attempt to find a cure, a preventive treatment and efficient early diagnosis tools. On the other hand, the risen white flag should worry the same researchers: it is the sign that, in general, a wrong approach has been probably pursued. The failure of the current clinical trials relies on the attempt to treat the neurodegenerative process targeting single effectors of the Disease. It is becoming more and more evident that, as a multifactorial disease, Alzheimer’s has to be considered as a systemic pathology in which different biochemical and molecular pathways are involved as well as different cellular population or even different tissues. The road to approach to Alzheimer’s through systems biology or medicine is maybe still long, but we already have the background to consider the role of the whole brain microenvironment in the onset and progression of the disease. Glial cells, brain vasculature and blood-brain-barrier clearly play a relevant role in Alzheimer’s Disease through the production of several molecules that can influence the (patho)physiology of the neuronal cells. Particularly promising seems the study of the possible epigenetic modifications induced in neurons by the alterations of the brain microenvironment.
Abbott A 2018, The brain inflammed. Nature. vol. 556, pp. 426-428.
Alzheimer’s Association 2017, 2017 Alzheimer's disease facts and figures. Alzheimer’s and Dementia. vol. 12, no. 4, pp.459-509.
Anand P, Singh B 2013, A review on cholinesterase inhibitors for Alzheimer’s disease. Archives of Pharmacological Research. vol. 36, no. 4, pp. 375-399.
Barnard ND, Bush AI, Ceccarelli A, Cooper J, de Jager CA, Erickson KI, Fraser G, Kesler S, Levin SM, Lucey B, Morris MC, Squitti R 2014, Dietary and lifestyle guidelines for the prevention of Alzheimer's disease. Neurobiology of Aging. vol. 35, Suppl 2, pp.S74-S78.
Bizzarri M, Cucina A 2014, Tumor and the microenvironment: a chance to reframe the paradigm of carcinogenesis? Biomedical Research International. vol. 2014, pp.934038.
Braak H, Braak E, Grundke-Iqbal I, Iqbal K 1986, Occurrence of neurophil threads in the senile human brain and in Alzheimer’s disease: a third location of paired helical filaments outside of neurofibrillary tangles and neuritic plaques. Neuroscience Letters. vol. 65, pp. 351-355.
Businaro R, Ippoliti F, Ricci S, Canitano N, Fuso A 2012, Alzheimer's disease promotion by obesity: induced mechanisms-molecular links and perspectives. Current Gerontology and Geriatric Research. vol. 2012, pp. 986823.
Castrillo JI, Lista S, Hampel H, Ritchie CW 2018, Systems Biology Methods for Alzheimer's Disease Research Toward Molecular Signatures, Subtypes, and Stages and Precision Medicine: Application in Cohort Studies and Trials. Methods in Molecular Biology. vol. 1750, pp. 31-66.
Chen Z, Zhong C 2014, Oxidative stress in Alzheimer's disease. Neuroscience Bulletin. vol. 30, no. 2, pp. 271-281.
Chow VW, Mattson MP, Wong PC, Gleichmann M. 2010, An overview of APP processing enzymes and products. Neuromolecular Medicine. vol. 12, no. 1, pp.1-12.
Dai MH, Zheng H, Zeng LD, Zhang Y 2017 The genes associated with early-onset Alzheimer's disease. Oncotarget. Vol. 9, no. 19, pp. 15132-15143.
de Bruijn RF, Ikram MA 2014, Cardiovascular risk factors and future risk of Alzheimer's disease. BMC Medicine. vol. 12, pp.130.
De Strooper B 2000, Nature. vol. 405, pp. 627-629.
De Strooper B, Chávez Gutiérrez L 2015, Learning by failing: ideas and concepts to tackle γ-secretases in Alzheimer's disease and beyond. Annual Review in Pharmacol ogy and Toxicology. vol. 55, pp. 419-437.
Dinicola S, Proietti S, Cucina A, Bizzarri M, Fuso A 2017, Alpha-Lipoic Acid Downregulates IL-1β and IL-6 by DNA Hypermethylation in SK-N-BE Neuroblastoma Cells. Antioxidants (Basel). vol. 6, no. 4, pp. E74.
Fuso A, Scarpa S 2011, One-carbon metabolism and Alzheimer's disease: is it all a methylation matter? Neurobiology of Aging. vol. 32, no. 7, pp. 1192-1195.
Fuso A, Nicolia V, Ricceri L, Cavallaro RA, Isopi E, Mangia F, Fiorenza MT, Scarpa S 2012, S-adenosylmethionine reduces the progress of the Alzheimer-like features induced by B-vitamin deficiency in mice. Neurobiology of Aging. vol. 33, no. 7, pp. 1482.e1-16.
Fuso A 2018, “Aging and Disease: the epigenetic bridge.” In TO Tollefsbol (eds.), Epigenetics of Human Disease, II edition, pp. 935-974. Elsevier, Academic Press.
Gold M 2017, Phase II clinical trials of anti-amyloid β antibodies: When is enough, enough? Alzheimers and Dementia. vol. 3, no. 3, pp. 402-409.
Heneka MT, Kummer MP, Latz E 2014, Innate immune activation in neurodegenerative disease. Nature Reviews on Immunology. vol. 14, pp. 463–477.
Imtiaz B, Tolppanen AM, Kivipelto M, Soininen H 2014, Future directions in Alzheimer's disease from risk factors to prevention. Biochem Pharmacology. Vol. 88, no. 4, pp.661-670.
Kzhyshkowska J, Bizzarri M, Apte R, Cherdyntseva N 2017, Editorial: Targeting of Cancer Cells and Tumor Microenvironment: Perspectives for Personalized Therapy. Current Pharmaceutical Design. vol. 23, no. 32, pp. 4703-4704.
Latta CH, Brothers HM, Wilcock DM 2015, Neuroinflammation in Alzheimer's disease; A source of heterogeneity and target for personalized therapy. Neuroscience. vol. 302, pp. 103-111.
Li X, Bao X, Wang R 2016, Neurogenesis-based epigenetic therapeutics for Alzheimer's disease. Molecular Medicine Reports. vol. 14, no. 2, pp. 1043-1053.
López-González I, Schlüter A, Aso E, Garcia-Esparcia P, Ansoleaga B, LLorens F, Carmona M, Moreno J, Fuso A, Portero-Otin M, Pamplona R, Pujol A, Ferrer I 2015, Neuroinflammatory signals in Alzheimer disease and APP/PS1 transgenic mice: correlations with plaques, tangles, and oligomeric species. J Neuropathology and Experimental Neurology. vol. 74, no. 4, pp. 319-44.
Lu A, Magupalli VG, Ruan J, Yin Q, Atianand MK, Vos MR, Schröder GF, Fitzgerald KA, Wu H, Egelman EH 2014, Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes. Cell. vol. 156, pp. 1193–1206.
Mastroeni D, Grover A, Delvaux E, Whiteside C, Coleman PD, Rogers J 2011, Epigenetic mechanisms in Alzheimer's disease. Neurobiology of Aging. vol. 32, no. 7, pp, 1161-1180.
McCormick MA, Promislow DEL 2017, Recent Advances in the Systems Biology of Aging. Antioxidant and Redox Signaling. In press. doi: 10.1089/ars.2017.7367
Mendez MF, Paholpak P, Lin A, Zhang JY, Teng E 2015, Prevalence of Traumatic Brain Injury in Early Versus Late-Onset Alzheimer's Disease. J Alzheimers Disease.vol. 47, no. 4, pp. 985-993.
Mudher A, Lovestone S 2002, Alzheimer's disease-do tauists and baptists finally shake hands? Trends in Neuroscience. vol. 25, no. 1, pp. 22-26.
Nesi G, Sestito S, Digiacomo M, Rapposelli S 2017, Oxidative Stress, Mitochondrial Abnormalities and Proteins Deposition: Multitarget Approaches in Alzheimer’s Disease. Current Topics in Medicinal Chemistry. vol. 17, no. 27, pp. 3062-3079.
Nicolia V, Cavallaro RA, López-González I, Maccarrone M, Scarpa S, Ferrer I, Fuso A. 2017, DNA Methylation Profiles of Selected Pro-Inflammatory Cytokines in Alzheimer Disease. J Neuropathology and Experimental Neurology. vol. 76, no. 1, pp. 27-31.
Nicolia V, Lucarelli M, Fuso A 2015, Environment, epigenetics and neurodegeneration: Focus on nutrition in Alzheimer's disease. Experimental Gerontology. vol. 68, pp. 8-12.
Nicolia V, Fuso A, Cavallaro RA, Di Luzio A, Scarpa S 2010, B vitamin deficiency promotes tau phosphorylation through regulation of GSK3beta and PP2A. J of Alzheimers Disease. vol. 19, no. 3, pp. 895-907.
Pérez DI, Martínez A, Gil C, Campillo NE 2015, From Bitopic Inhibitors to Multitarget Drugs for the Future Treatment of Alzheimer’s Disease. Current Medicinal Chemistry. vol. 22, no. 33, pp. 3789-3806.
Regen F, Hellmann-Regen J, Costantini E, Reale M 2017, Neuroinflammation and Alzheimer's Disease: Implications for Microglial Activation. Current Alzheimer Research. vol. 14, no. 11, pp. 1140-1148.
Rollo JL, Banihashemi N, Vafaee F, Crawford JW, Kuncic Z, Holsinger RM 2016, Unraveling the mechanistic complexity of Alzheimer's disease through systems biology. Alzheimers and Dementia. vol. 12, no. 6, pp. 708-718.
Rosini M, Simoni E, Caporaso R, Minarini A 2016, Multitarget strategies in Alzheimer's disease: benefits and challenges on the road to therapeutics. Future in Medicinal Chemistry. vol. 8, no. 6, pp. 697-711.
Salminen A, Kaarniranta K, Kauppinen A 2018, The potential importance of myeloid-derived suppressor cells (MDSCs) in the pathogenesis of Alzheimer's disease. Cell Molecular Life Science. In press, doi: 10.1007/s00018-018-2844-6.
Schneider LS, Mangialasche F, Andreasen N, Feldman H, Giacobini E, Jones R, Mantua V, Mecocci P, Pani L, Winblad B, Kivipelto M 2014, Clinical trials and late-stage drug development for Alzheimer's disease: an appraisal from 1984 to 2014. J Internal Medicine. vol. 275, no. 3, pp. 251-283.
Selkoe DJ 2000, Toward a comprehensive theory for Alzheimer’s disease. Hypothesis: Alzheimer’s disease is caused by the cerebral accumulation and cytotoxicity of amyloid beta-protein. Annals of NY Academy of Sciences. vol. 924, pp. 17-25.
Soejitno A, Tjan A, Purwata TE 2015, Alzheimer's Disease: Lessons Learned from Amyloidocentric Clinical Trials. CNS Drugs. vol. 29, no. 6, pp. 487-502.
Sun J, Feng X, Liang D, Duan Y, Lei H 2012, Down-regulation of energy metabolism in Alzheimer's disease is a protective response of neurons to the microenvironment. J Alzheimers Disease. vol. 28, no. 2, pp. 389-402.
Tam C, Wong JH, Ng TB, Tsui SK, Zuo T 2018, Drugs for targeted therapies of Alzheimer's disease. Current Medical Chemistry. In press (doi:10.2174/ 0929867325666180430150940).
Tepper K, Biernat J, Kumar S, Wegmann S, Timm T, Hübschmann S, Redecke L, Mandelkow EM, Müller DJ, Mandelkow E 2014, Oligomer formation of tau protein hyperphosphorylated in cells. J Biological Chemisgry. vol. 289, no. 49, pp. 4389-4407.
Toyn JH, Ahlijanian MK 2014, Interpreting Alzheimer's disease clinical trials in light of the effects on amyloid-β. Alzheimers Research and Therapy. vol. 6, no. 2, pp. 14.
Trojanowski JQ 2002, Tauists, Baptists, Syners, Apostates, and new data. Annals of Neurology. vol. 52, no. 3, pp. 263-265.
Venegas C, Kumar S, Franklin BS, Dierkes T, Brinkschulte R, Tejera D, Vieira-Saecker A, Schwartz S, Santarelli F, Kummer MP, Griep A, Gelpi E, Beilharz M, Riedel D, Golenbock DT, Geyer M, Walter J, Latz E, Heneka MT 2017, Nature. vol. 552, pp. 355–361.
Wang WY, Tan MS, Yu JT, Tan L 2015, Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease.Translational Medicine. vol. 3, no. 10, pp. 136.
Wilkins JM, Trushina E 2018, Application of Metabolomics in Alzheimer's Disease. Annals Frontiers in Neurology. vol. 12, no. 8, pp. 719.
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