Liposomal vaccines with conformation-specific amyloid peptide antigens define immune response and efficacy in APP transgenic mice

Abstract

We investigated the therapeutic effects of two different versions of A␤ 1-15 (16) liposome-based vaccines. Inoculation of APP-V717IxPS-1 (APPxPS-1) double-transgenic mice with tetrapalmitoylated amyloid 1-15 peptide (palmA␤ 1-15), or with amyloid 1-16 peptide (PEG-A␤ 1-16) linked to a polyethyleneglycol spacer at each end, and embedded within a liposome membrane, elicited fast immune responses with identical binding epitopes. PalmA␤ 1-15 liposomal vaccine elicited an immune response that restored the memory defect of the mice, whereas that of PEG-A␤ 1-16 had no such effect. Immunoglobulins that were generated were predominantly of the IgG class with palmA␤ 1-15, whereas those elicited by PEG-A␤ 1-16 were primarily of the IgM class. The IgG subclasses of the antibodies generated by both vaccines were mostly IgG2b indicating noninflammatory Th2 isotype. CD and NMR revealed predominantly ␤-sheet conformation of palmA␤1-15 and random coil of PEG-A␤ 1-16. We conclude that the association with liposomes induced a variation of the immunogenic structures and thereby different immunogenicities. This finding supports the hypothesis that Alzheimer's disease is a ''conformational'' disease, implying that antibodies against amyloid sequences in the ␤-sheet conformation are preferred as potential therapeutic agents.Alzheimer's disease ͉ ␤-amyloid ͉ vaccine C linical manifestations of Alzheimer's disease (AD) include progressive memory loss, cognitive impairment, confusion, and personality changes. The major neuropathological changes in the brains of AD patients are senile plaques and neurofibrillar tangles causing progressive neuronal dysfunction. These pathological alterations are likely causally involved in eventual neuronal death, particularly in brain regions related to memory and cognition (1-4). Senile plaques are formed predominantly by the ␤-amyloid peptide A␤ 1-42 that is coiled and ␣-helical in its soluble form but, upon conformational transition, aggregates into ␤-sheeted multimers. The monomeric A␤ peptide is a physiological metabolite of the large amyloid precursor protein (APP, 695-770 aa) that undergoes processing by several sequential proteolytic steps (5). The A␤ 1-42 aggregates are proposed to play the key role in the pathogenesis of AD (6). In transgenic animals that overexpress mutant human APP, anti-A␤-specific antibodies decreased the A␤ burden and improved memory after either passive (7-11) or active (12-18) immunization.We previously demonstrated that i.p. inoculation of tetrapalmitoylated A␤1-16 reconstituted in liposomes to transgenic NORBA mice elicited significant titers of anti-A␤ antibodies, that solubilized amyloid fibers in vitro and pancreatic A␤ plaques in vivo (19). To circumvent T cell-mediated immune responses known to be causatively involved in the adverse events of meningoencephalitis of AD patients immunized with A␤1-42 (20-22), the A␤1-16 and 1-15 sequences were used for immunization of APPxPS1 double-transgenic mice (23) because strong T cell epitopes are located more toward the C-te...

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

“…An array of Aβ1-15 sequences are anchored to the surface of liposomes adopting an aggregated β-sheet structure that acts as conformational epitope. In preclinical studies, repeated subcutaneous injection of ACI-24 into AD transgenic mice generated high titers of anti-Aβ antibodies, decreasing the concentration of insoluble Aβ1-40 and Aβ1-42, and of soluble Aβ1-42 [72,73]. ACI-24 also improved novel object recognition without triggering proinflammatory responses [73].…”

“…In preclinical studies, repeated subcutaneous injection of ACI-24 into AD transgenic mice generated high titers of anti-Aβ antibodies, decreasing the concentration of insoluble Aβ1-40 and Aβ1-42, and of soluble Aβ1-42 [72,73]. ACI-24 also improved novel object recognition without triggering proinflammatory responses [73]. Finally, DNA vaccines against Aβ1-42 [98,99], alone or in combination with protein antigens [100,101], have shown promising results at the preclinical stage.…”

Brain Drug Delivery Systems for Neurodegenerative Disorders

“…Some years later, the same author tested two different vaccines using epitopes of the Aβ protein embedded within a liposome membrane; the tetrapalmitoylated amyloid (1-15) peptide, and the amyloid (1-16) peptide linked to a polyethyleneglycol spacer at each end. Both vaccines were administered also by the intraperitoneal route into APPxPS-1 double transgenic mice, eliciting a fast immune response [108]. The association with liposomes induced some changes in the immunogenic structures that caused different immunogenicities.…”

Chemical and Physical Approaches for the Treatment of Alzheimer's Disease

“…However, ACC-001 has been discontinued from development since May 9, 2013 [50]. A Phase 1/2 trial of ACI-24 began in the year of 2009, to explore the safety, efficacy, and immunogenicity of this liposome vaccine, which showed positive consequence in AD transgenic mice [51]. Another compound UB311 was undergone a Phase 1 study in Taiwan to address the safety, tolerability and immunogenicity issues with favourable results obtained, including positive antibody responses and elevated neuropsychological outcomes without any serious side effects [52].…”