Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia in elderly 
. A characteristic of the disease is formation of plaques in the brain or in brain blood vessels. These plaques originate from a membrane-bound protein, amyloid precursor protein (APP). An α-helical fragment of 39–42 amino acid residues is cleaved by β- and γ-secretases from APP thus forming a soluble amyloid β (Aβ) peptide. Soluble Aβ initially adopts an extended conformation but at high concentrations, soluble Aβ will undergo conformational changes and form oligomers, protofibrils, and fibrils. In AD, fibrillar Aβ is deposited in the brain as amyloid plaques, which is one of the main neuropathological hallmarks of the disease. However, accumulating studies suggest that the soluble oligomeric Aβ instead of insoluble Aβ in amyloid plaques is the culprit in AD 
and therapeutic approaches aimed at preventing the formation of these oligomeric isoforms may be able to reduce the progression of the disease. In line with this concept, immunization of transgenic mice 
with a suspension of “pre-aggregated” Aβ(1–42) and the adjuvant quillaja saponin 21 appeared to be beneficial. Based on these results, a phase I clinical trial was started. Antibodies present in human sera recognized plaques and Aβ deposits in brain blood vessels 
. The antibodies did not recognize APP or soluble Aβ. In the following phase II clinical trial, 20% of the vaccine recipients generated anti-Aβ antibody titers. Unfortunately, this trial had to be terminated since 6% of the patients developed meningoencephalitis as a vaccine-related side effect. This side effect was caused by a cellular inflammatory reaction, attributed to a T helper cell type 1 response to epitopes located in the central and C-terminal part of Aβ(1–42) 
Multiple ongoing studies aim at improving the Aβ vaccination strategy 
. The use of T helper cell type 2 directing adjuvants 
or the use of formulations without any adjuvant 
are under investigation. In addition, it has been proposed to use C-terminally truncated Aβ peptides 
or peptide mimics (affitopes) of the N-terminus 
. Antibodies induced by Aβ(1–42) are dominantly directed against the linear N-terminal epitope 
, although generation of conformation-specific antibodies against other regions within aggregated Aβ has been reported 
. A disadvantage of a vaccine against the N-terminus of Aβ is that it will interfere with the normal physiological processing of APP. It may not be without risk to administer such a vaccine before onset of symptoms of AD.
By targeting an immune response exclusively on misfolded Aβ the undesired response against the N-terminus of Aβ may be avoided all together. A structural model of fibrillar Aβ(1–42) predicts folding of monomeric Aβ(1–42) into a cross-β unit. Two antiparallel extended β-strands, residues 11–25 and 28–42, are connected via a sharp bend around amino acid residues S26 and N27 
. shows a simplification of the original model. A recent study of a particular oligomer of N-Met-Aβ(1–42) suggests a bend around the sequence V24
Early folding of human amyloid β (Aβ), around S26 and N27.
The models of folded Aβ show some resemblance with the β-turn structure in surface loops of meningococcal outer membrane protein PorA. Previously, we have stabilized the β-turn conformation of small meningococcal peptides by adding an artificial sequence YNGK′, in which K′ is a modified lysine residue for selective conjugation to a carrier protein, followed by main chain (“head to tail”) amide cyclization 
. Likewise, it appeared possible to prepare small cyclic peptides mimicking the turn in folded Aβ. A panel of cyclic decameric and undecameric peptides spanning six or seven residues from the region 21–31 of Aβ and YNGK′ was prepared and conjugated to tetanus toxoid (TTd). The conjugates were used for immunization of mice. A tetanus toxoid-conjugate of one of the peptides, cyclo[Aβ(22–28)-YNGK′], elicited antibodies that specifically recognized misfolded Aβ.