Tohoku J. Exp. Med., 2010, 220(2)

Invited Review for the 90^th Anniversary

Immunization Therapy for Alzheimer Disease: A Comprehensive Review of Active Immunization Strategies

TAKESHI TABIRA¹

¹Department of Diagnosis, Prevention and Treatment of Dementia, Graduate School of Juntendo University, Tokyo, Japan

Based on the amyloid cascade hypothesis, various strategies targeting amyloid β protein (Aβ) have been invented for prevention and treatment of Alzheimer disease (AD). Active and passive immunizations with Aβ and Aβ antibodies successfully reduced AD pathology and improved cognitive functions in an AD mouse model. However, active immunization with AN-1792, a mixture of Aβ1-42 peptide and adjuvant QS21 induced autoimmune encephalitis in humans. Surprisingly, although AN-1792 cleared senile plaque amyloid, it showed no benefit in humans. It is speculated that AN-1792 failed in deleting more toxic forms of Aβ such as oligomers and intracellular Aβ, suggesting that newly developing vaccines should delete these toxic molecules. Since T cell epitopes exist mainly in the C-terminal portion of Aβ, vaccines using shorter N-terminal peptides are under development. In addition, since T helper 1 (Th1) immune responses activate encephalitogenic T cells and induce continuous inflammation in the central nervous system, vaccines inducing Th2 immune responses seem to be more promising. These are N-terminal short Aβ peptides with Th2 adjuvant or Th2-stimulating molecules, DNA vaccines, recombinant viral vector vaccines, recombinant vegetables and others. Improvement of vaccines will be also achieved by the administration method, because Th2 immune responses are mainly induced by mucosal or trans-cutaneous immunizations. Here I review recent progress in active immunization strategies for AD.

keywords —— Alzheimer; vaccine; immunotherapy; autoimmune; T helper 1; T helper 2