Immunization with a Nontoxic/Nonfibrillar Amyloid-β Homologous Peptide Reduces Alzheimer's Disease-Associated Pathology in Transgenic Mice

Abstract

Transgenic mice with brain amyloid-beta (Abeta) plaques immunized with aggregated Abeta1-42 have reduced cerebral amyloid burden. However, the use of Abeta1-42 in humans may not be appropriate because it crosses the blood brain barrier, forms toxic fibrils, and can seed fibril formation. We report that immunization in transgenic APP mice (Tg2576) for 7 months with a soluble nonamyloidogenic, nontoxic Abeta homologous peptide reduced cortical and hippocampal brain amyloid burden by 89% (P = 0.0002) and 81% (P = 0.0001), respectively. Concurrently, brain levels of soluble Abeta1-42 were reduced by 57% (P = 0.0019). Ramified microglia expressing interleukin-1beta associated with the Abeta plaques were absent in the immunized mice indicating reduced inflammation in these animals. These promising findings suggest that immunization with nonamyloidogenic Abeta derivatives represents a potentially safer therapeutic approach to reduce amyloid burden in Alzheimer's disease, instead of using toxic Abeta fibrils.

Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report

“…Comparison with unimmunized cases of AD (n = 7) revealed the following unusual features in the immunized case, despite diagnostic neuropathological features of AD: (i) there were extensive areas of neocortex with very few Aβ plaques; (ii) those areas of cortex that were devoid of Aβ plaques contained densities of tangles, neuropil threads and cerebral amyloid angiopathy (CAA) similar to unimmunized AD, but lacked plaque-associated dystrophic neurites and astrocyte clusters; (iii) in some regions devoid of plaques, Aβ-immunoreactivity was associated with microglia; (iv) T-lymphocyte meningoencephalitis was present; and (v) cerebral white matter showed infiltration by macrophages. Findings (i)-(iii) strongly resemble the changes seen after Aβ immunotherapy in mouse models of AD [1][2][3][4][5][6] and suggest that the immune response generated against the peptide elicited clearance of Aβ plaques in this patient. The T-lymphocyte meningoencephalitis is likely to correspond to the side effect seen in some other patients who received AN-1792 (refs.…”

A non-toxic ligand for voxel-based MRI analysis of plaques in AD transgenic mice

“…In the current study we used K6-A␤1-30 chelated to gadolinium via incorporation of DPTA at the amino terminus. In our previously published studies we used K6-A␤1-30 as a vaccine therapy in AD model mice and have shown that this peptide is both non-toxic and non-fibrillogenic (Sigurdsson et al, 2001;Asuni et al, 2006). In the current study we have also demonstrated that this A␤ homologous peptide is nontoxic when labeled with chelated Gd (Fig.…”

“…We designed these homologous peptides so that they still have a high binding affinity to wild-type A␤ peptides and also have a similar BBB permeability. In prior studies we have shown that these A␤ homologous peptides do not self-assemble or promote the fibrillization of endogenous A␤ peptides (Asuni et al, 2006;Sigurdsson et al, 2001Sigurdsson et al, , 2004a). In the current study we used K6-A␤1-30 chelated to gadolinium via incorporation of DPTA at the amino terminus.…”

“…The potential neurotoxicity of the MRI ligand, Gd-DTPA-K6A␤1-30, was evaluated at 6 days in a human neuroblastoma cell line (SK-N-SH) using the MTT assay as described previously (Sigurdsson et al, 2001). A␤1-42, K6A␤1-30 and DTPA-K6A␤1-30 were used as controls.…”

“…Hence, we developed a compound, Gd-DTPA-K6A␤1-30, that does not form amyloid aggregates and is non-toxic while maintaining high affinity for A␤. We have previously used K6A␤1-30 and related derivatives as experimental vaccines against AD (Sigurdsson et al, 2001(Sigurdsson et al, , 2004a. In this report we have evaluated the utility of this A␤ homologous peptide, which has therapeutic potential as a vaccine, for a dual use as a MRI contrast agent, when coupled with gadolinium.…”