Glatiramer acetate fights against Alzheimer’s disease by inducing dendritic-like microglia expressing insulin-like growth factor 1

doi:10.1073/pnas.0604681103

Glatiramer acetate fights against Alzheimer’s disease by inducing dendritic-like microglia expressing insulin-like growth factor 1

*Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel;
^‡Kaplan Medical Center, Rehovot 76100, Israel; and
^§Ministry of Health, Mental Health Center, Anxiety and Stress Research Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel

Communicated by Michael Sela, Weizmann Institute of Science, Rehovot, Israel, June 7, 2006
↵ ^†O.B. and M.K.-H. contributed equally to this work. (received for review April 6, 2006)

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 β-amyloid, and characterized as CD11b⁺/CD11c⁻/MHC class II⁻/TNF-α⁺ cells, impeded neurogenesis from adult neural stem/progenitor cells, whereas CD11b⁺/CD11c⁺/MHC class II⁺/TNF-α⁻ microglia, a phenotype induced by IL-4, counteracted the adverse β-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.

Footnotes

^¶To whom correspondence should be addressed. E-mail: michal.schwartz{at}weizmann.ac.il
Author contributions: O.B., M.K.-H., E.O., and M.S. designed research; O.B., M.K.-H., G.K., E.O., G.L., and H.C. performed research; O.B., M.K.-H., G.K., E.O., G.L., and H.C. analyzed data; and O.B., M.K.-H., E.O., and M.S. wrote the paper.
Conflict of interest statement: No conflicts declared.
Abbreviations:

IGF1,

insulin-like growth factor 1;

MHC-II,

MHC class II;

AD,

Alzheimer’s disease;

Tg,

transgenic;

GA,

glatiramer acetate;

NPC,

neural stem/progenitor cell;

MWM,

Morris water maze;

Aβ,

amyloid β;

IB-4,

isolectin B4.