This review discusses the molecular basis and current status of immunotherapeutic strategies for prevention and treatment of
Alzheimer's disease (AD). From the molecular view-point AD belongs to the group of conformational diseases. In-vitro studies demonstrated that
monoclonal antibodies could modulate the conformation of Abeta
peptides with subsequent inhibition of
amyloid fibrils formation and aggregation. The efficacy of this approach was then successfully proved in the murine models of AD using predominantly Abeta (42)
peptide as immunogen. Immunisation of the young animals essentially prevented the development of
beta-amyloid plaques formation and of concomittant neuropathology. Treatment of the older animals markedly reduced the pre-existing AD-like neuropathology. Immunisation was capable of preventing cognitive deficits in the young transgenic animals and improve the memory and behavioural disturbances in the older animals. Measurement of specific murine immunoglobulines in Abeta-vaccinated mice demonstrated a predominant
IgG1 and
IgG2b isotypes, suggesting a type 2 (T (H)2) T-helper cell immune response, which drives humoral immunity. The intensity of the immune response depended on transgenic animals genotype, dose, frequency and route of immunogen administration. The mechanism of
antibodies action in transgenic animals consists of inducing conformational and solubility changes in Abeta
peptides as well as their peripheral sink. Lymphocyte proliferation assays using Abeta
peptides and splenocytes from vaccinated mice demonstrated that
vaccine specifically stimulated
T-cell epitopes present within the Abeta-
peptide. Extensive quantitative morphological, histochemical and molecular analysis of brain tissue from several species of Abeta-immunised transgenic and non-transgenic animals showed no evidence of autoimmune reaction, complement activation or cross-reaction. No pathological changes were found in all other organs, including the kidney. Neuropathologic examination in a patient treated with
vaccine revealed similar vaccination effects as in experimental animals. An aseptic meningo-
encephalitis was reported in 5 % of patients included in a clinical trial in which a
vaccine containing Abeta (42)
peptide (
AN1792) was administered intramuscularly. The causal relationship to the
vaccine administration cannot be excluded since in transgenic mice a transient microglia activation was seen. However, this relatively infrequent although severe adverse effect points to a possible participation of some actually unknown risk factors in the treated patients. With regard to the rapid progress in biotechnology, especially in the
vaccines technology, the development of efficacious and safe immunogens as well as of new vaccination techniques for immuntherapy of AD can be expected in the next future.