Faculty Bibliography

Alzheimer's disease (AD) is associated with accumulation of beta-amyloid (Abeta). A major genetic risk factor for sporadic AD is inheritance of the apolipoprotein (apo) E4 allele. ApoE can act as a pathological chaperone of Abeta, promoting its conformational transformation from soluble Abeta into toxic aggregates. We determined if blocking the apoE/Abeta interaction reduces Abeta load in transgenic (Tg) AD mice. The binding site of apoE on Abeta corresponds to residues 12 to 28. To block binding, we synthesized a peptide containing these residues, but substituted valine at position 18 to proline (Abeta12-28P). This changed the peptide's properties, making it non-fibrillogenic and non-toxic. Abeta12-28P competitively blocks binding of full-length Abeta to apoE (IC(50) = 36.7 nmol). Furthermore, Abeta12-28P reduces Abeta fibrillogenesis in the presence of apoE, and Abeta/apoE toxicity in cell culture. Abeta12-28P is blood-brain barrier-permeable and in AD Tg mice inhibits Abeta deposition. Tg mice treated with Abeta12-28P for 1 month had a 63.3% reduction in Abeta load in the cortex (P = 0.0043) and a 59.5% (P = 0.0087) reduction in the hippocampus comparing to age-matched control Tg mice. Antibodies against Abeta were not detected in sera of treated mice; therefore the observed therapeutic effect of Abeta12-28P cannot be attributed to an antibody clearance response. Our experiments demonstrate that compounds blocking the interaction between Abeta and its pathological chaperones may be beneficial for treatment of beta-amyloid deposition in AD

Immunization with amyloid-beta (Abeta) 1-42 has been shown to reduce amyloid burden and improve cognition in Alzheimer's disease (AD) model mice. In a human trial, possible cognitive benefit was found but in association with significant toxicity in a minority of patients. We proposed that immunization with nonfibrillogenic Abeta derivatives is much less likely to produce toxicity and have previously shown that one such derivative (K6Abeta1-30) can reduce amyloid burden in mice to a similar extent as Abeta1-42. Here, we immunized AD model mice (Tg2576) with Abeta1-30[E18E19] or with K6Abeta1-30[E18E19]. These peptides were designed to be nontoxic and to produce less T-cell response, which has been linked to toxicity. K6Abeta1-30[E18E19] induced primarily an IgM response, whereas Abeta1-30[E18E19] induced an IgG titer that was lower than previously seen with K6Abeta1-30 or Abeta1-42. However, both treated animal groups performed better than Tg controls in the radial arm maze. Amyloid burden was similar in Abeta1-30[E18E19]-vaccinated mice and their Tg controls, whereas the number of medium and small sized plaques was reduced (29-34%) in K6Abeta1-30[E18E19]-immunized mice compared with Tg controls. Amyloid burden in these mice correlated inversely with plasma IgM levels. The cognitive benefit and amyloid reduction in the K6Abeta1-30[E18E19]-vaccinated mice are likely to be related to peripheral clearance of Abeta, because IgM does not cross the blood-brain barrier because of its large size. Our results indicate that these nontoxic Abeta derivatives produce an attenuated antibody response, which is less likely to be associated with negative side effects while having cognitive benefits