Based on the
amyloid cascade hypothesis, various strategies targeting
amyloid beta protein (Abeta) have been invented for prevention and treatment of
Alzheimer disease (AD). Active and passive immunizations with Abeta and Abeta
antibodies successfully reduced AD pathology and improved cognitive functions in an AD mouse model. However, active immunization with
AN-1792, a mixture of Abeta1-42
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 Abeta such as oligomers and intracellular Abeta, suggesting that newly developing
vaccines should delete these toxic molecules. Since
T cell epitopes exist mainly in the C-terminal portion of Abeta,
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 Abeta
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.