Glatiramer Acetate Fights Against Alzheimer's Disease by Inducing Dendritic-like Microglia Expressing Insulin-like Growth Factor 1

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2006 Jul 26

PMID 16864778

Citations 169

Authors

Oleg Butovsky

Maya Koronyo-Hamaoui

Gilad Kunis

Eran Ophir

Gennady Landa

Hagit Cohen

Michal Schwartz

Affiliations

Soon will be listed here.

Abstract

Alzheimer's disease (AD) is characterized by plaque formation, neuronal loss, and cognitive decline. The functions of the local and systemic immune response in this disease are still controversial. Using AD double-transgenic (APP/PS1) mice, we show that a T cell-based vaccination with glatiramer acetate, given according to a specific regimen, resulted in decreased plaque formation and induction of neurogenesis. It also reduced cognitive decline, assessed by performance in a Morris water maze. The vaccination apparently exerted its effect by causing a phenotype switch in brain microglia to dendritic-like (CD11c) cells producing insulin-like growth factor 1. In vitro findings showed that microglia activated by aggregated beta-amyloid, and characterized as CD11b(+)/CD11c(-)/MHC class II(-)/TNF-alpha(+) cells, impeded neurogenesis from adult neural stem/progenitor cells, whereas CD11b(+)/CD11c(+)/MHC class II(+)/TNF-alpha(-) microglia, a phenotype induced by IL-4, counteracted the adverse beta-amyloid-induced effect. These results suggest that dendritic-like microglia, by facilitating the necessary adjustment, might contribute significantly to the brain's resistance to AD and argue against the use of antiinflammatory drugs.

Citing Articles

Immune mechanisms and shared immune targets in neurodegenerative diseases.

Weiner H Nat Rev Neurol. 2024; 21(2):67-85.

PMID: 39681722 DOI: 10.1038/s41582-024-01046-7.

The signaling landscape of insulin-like growth factor 1.

Khan M, Zugaza J, Torres Aleman I J Biol Chem. 2024; 301(1):108047.

PMID: 39638246 PMC: 11748690. DOI: 10.1016/j.jbc.2024.108047.

Microglia Signatures: A Cause or Consequence of Microglia-Related Brain Disorders?.

Mirarchi A, Albi E, Arcuri C Int J Mol Sci. 2024; 25(20).

PMID: 39456734 PMC: 11507570. DOI: 10.3390/ijms252010951.

Spatial dynamics of mammalian brain development and neuroinflammation by multimodal tri-omics mapping.

Zhang D, Rubio Rodriguez-Kirby L, Lin Y, Song M, Wang L, Wang L bioRxiv. 2024; .

PMID: 39091821 PMC: 11291146. DOI: 10.1101/2024.07.28.605493.

Rotating magnetic field improved cognitive and memory impairments in a sporadic ad model of mice by regulating microglial polarization.

Li M, Yu Q, Anayyat U, Yang H, Wei Y, Wang X Geroscience. 2024; 46(6):6229-6256.

PMID: 38904930 PMC: 11493917. DOI: 10.1007/s11357-024-01223-y.

References

van Praag H, Kempermann G, Gage F . Neural consequences of environmental enrichment. Nat Rev Neurosci. 2001; 1(3):191-8. DOI: 10.1038/35044558. View

Duda P, Schmied M, Cook S, Krieger J, Hafler D . Glatiramer acetate (Copaxone) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis. J Clin Invest. 2000; 105(7):967-76. PMC: 377485. DOI: 10.1172/JCI8970. View

Lichtenwalner R, Forbes M, Bennett S, Lynch C, Sonntag W, Riddle D . Intracerebroventricular infusion of insulin-like growth factor-I ameliorates the age-related decline in hippocampal neurogenesis. Neuroscience. 2001; 107(4):603-13. DOI: 10.1016/s0306-4522(01)00378-5. View

Hardy J, Selkoe D . The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002; 297(5580):353-6. DOI: 10.1126/science.1072994. View

Ziemssen T, Kumpfel T, Klinkert W, Neuhaus O, Hohlfeld R . Glatiramer acetate-specific T-helper 1- and 2-type cell lines produce BDNF: implications for multiple sclerosis therapy. Brain-derived neurotrophic factor. Brain. 2002; 125(Pt 11):2381-91. DOI: 10.1093/brain/awf252. View

Shors T, Townsend D, Zhao M, Kozorovitskiy Y, Gould E . Neurogenesis may relate to some but not all types of hippocampal-dependent learning. Hippocampus. 2002; 12(5):578-84. PMC: 3289536. DOI: 10.1002/hipo.10103. View

Kipnis J, Mizrahi T, Hauben E, Shaked I, Shevach E, Schwartz M . Neuroprotective autoimmunity: naturally occurring CD4+CD25+ regulatory T cells suppress the ability to withstand injury to the central nervous system. Proc Natl Acad Sci U S A. 2002; 99(24):15620-5. PMC: 137766. DOI: 10.1073/pnas.232565399. View

Angelov D, Waibel S, Guntinas-Lichius O, Lenzen M, Neiss W, Tomov T . Therapeutic vaccine for acute and chronic motor neuron diseases: implications for amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2003; 100(8):4790-5. PMC: 153634. DOI: 10.1073/pnas.0530191100. View

Iribarren P, Cui Y, Le Y, Ying G, Zhang X, Gong W . IL-4 down-regulates lipopolysaccharide-induced formyl peptide receptor 2 in murine microglial cells by inhibiting the activation of mitogen-activated protein kinases. J Immunol. 2003; 171(10):5482-8. DOI: 10.4049/jimmunol.171.10.5482. View

10.

Ekdahl C, Claasen J, Bonde S, Kokaia Z, Lindvall O . Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci U S A. 2003; 100(23):13632-7. PMC: 263865. DOI: 10.1073/pnas.2234031100. View

11.

Monje M, Toda H, Palmer T . Inflammatory blockade restores adult hippocampal neurogenesis. Science. 2003; 302(5651):1760-5. DOI: 10.1126/science.1088417. View

12.

Jankowsky J, Fadale D, Anderson J, Xu G, Gonzales V, Jenkins N . Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet. 2003; 13(2):159-70. DOI: 10.1093/hmg/ddh019. View

13.

Shaked I, Porat Z, Gersner R, Kipnis J, Schwartz M . Early activation of microglia as antigen-presenting cells correlates with T cell-mediated protection and repair of the injured central nervous system. J Neuroimmunol. 2003; 146(1-2):84-93. DOI: 10.1016/j.jneuroim.2003.10.049. View

14.

Rao M, Shetty A . Efficacy of doublecortin as a marker to analyse the absolute number and dendritic growth of newly generated neurons in the adult dentate gyrus. Eur J Neurosci. 2004; 19(2):234-46. DOI: 10.1111/j.0953-816x.2003.03123.x. View

15.

Aberg M, Aberg N, Hedbacker H, Oscarsson J, Eriksson P . Peripheral infusion of IGF-I selectively induces neurogenesis in the adult rat hippocampus. J Neurosci. 2001; 20(8):2896-903. PMC: 6772218. View

16.

Kipnis J, Yoles E, Porat Z, Cohen A, Mor F, Sela M . T cell immunity to copolymer 1 confers neuroprotection on the damaged optic nerve: possible therapy for optic neuropathies. Proc Natl Acad Sci U S A. 2000; 97(13):7446-51. PMC: 16565. DOI: 10.1073/pnas.97.13.7446. View

17.

Bard F, Cannon C, Barbour R, Burke R, Games D, Grajeda H . Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med. 2000; 6(8):916-9. DOI: 10.1038/78682. View

18.

Frenkel D, Maron R, Burt D, Weiner H . Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears beta-amyloid in a mouse model of Alzheimer disease. J Clin Invest. 2005; 115(9):2423-33. PMC: 1184038. DOI: 10.1172/JCI23241. View

19.

Bakalash S, Ben-Shlomo G, Shlomo G, Aloni E, Shaked I, Wheeler L . T-cell-based vaccination for morphological and functional neuroprotection in a rat model of chronically elevated intraocular pressure. J Mol Med (Berl). 2005; 83(11):904-16. DOI: 10.1007/s00109-005-0689-6. View

20.

Rivera E, Goldin A, Fulmer N, Tavares R, Wands J, de la Monte S . Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer's disease: link to brain reductions in acetylcholine. J Alzheimers Dis. 2005; 8(3):247-68. DOI: 10.3233/jad-2005-8304. View