Development of a safe oral Aβ vaccine using recombinant adeno-associated virus vector for Alzheimer's disease

Hara, Hideo; Monsonego, Alon; Yuasa, Katsutoshi; Adachi, Kayo; Xiao, Xiao; Takeda, Shin’ichi; Takahashi, K.; Weiner, Howard L.; Tabira, Takeshi

doi:10.3233/jad-2004-6504

Cited by 85 publications

(70 citation statements)

References 20 publications

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Section: Discussionmentioning

confidence: 87%

“…These observations highlighted the possibility that compounds that facilitate the Aβ43-to-Aβ40 and Aβ42-to-Aβ38 conversion might be beneficial for prevention and treatment of AD by decreasing not only Aβ42 but also Aβ43. In support of this notion, an oral vaccination with adeno-associated virus vector 20 carrying Aβ1-43 cDNA was reported to result in a marked reduction of Aβ burdens and improvement of behavioral performances in APP transgenic mice 40,41 .Although our original plan had been to establish APP Tg x homozygous PS1-R278I knockin mice, we also explored the possible utility of heterozygous PS1-R278I knockin mice, given that overexpression of APP in heterozygous PS1-R278I knockin MEFs resulted in selective elevation of Aβ43. Consistent with this, APP Tg x heterozygous PS1-R278I knockin mice exhibited short-term memory impairment, selective biochemical accumulation of Aβ43 at an early stage prior to plaque formation and significant acceleration of Aβ pathology thereafter as compared to single APP Tg mice.…”

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confidence: 88%

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Potent amyloidogenicity and pathogenicity of Aβ43

et al. 2011

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Aβ42 is known to be a primary amyloidogenic and pathogenic agent in Alzheimer's disease. However, the role of Aβ43, found just as frequently in patient brains, remains unresolved. We generated knockin mice containing a pathogenic presenilin-1 R278I mutation that causes overproduction of Aβ43. Homozygous mice exhibited embryonic lethality, indicating that the mutation involves loss of function. Crossing amyloid precursor protein transgenic mice with heterozygous mutant mice resulted in elevation of Aβ43 levels, impairment of short-term memory, and acceleration of Aβ pathology, accompanying pronounced accumulation of Aβ43 in plaque cores similar to the biochemical composition observed in patient brains. Consistently, Aβ43 showed a higher propensity to aggregate and was more neurotoxic than Aȕ42. Other pathogenic presenilin mutations also caused overproduction of Aβ43 in a manner correlating with Aβ42 and with age of disease onset. These findings indicate that Aβ43, an overlooked species, is potently amyloidogenic, neurotoxic, and abundant in vivo. 3 Alzheimer's disease, the most common form of dementia, is characterized by two pathological features in the brain, extracellular senile plaques and intracellular neurofibrillary tangles. Senile plaques consist of amyloid-β peptide (Aβ) generated from amyloid precursor protein (APP) through sequential proteolytic processing by β-secretase and γ-secretase. Two major forms of Aβ exist, Aβ40 and Aβ42, with Aβ42 being more neurotoxic due to its higher hydrophobicity, which results in faster oligomerization and aggregation 1 . A number of mutations associated with early-onset familial Alzheimer's disease (FAD) have been identified in the APP, PSEN1 and PSEN2 genes, and these mutations lead to accelerated production of Aβ42 or an increase in the Aβ42/Aβ40 ratio. Together these findings indicate that Aβ42 plays an essential role in the initiation of pathogenesis. However, the possible involvement of longer Aβ species that also exist in Alzheimer's disease brains has not yet been fully investigated.Thus far, various longer Aβ species, such as Aβ43, Aβ45, Aβ48, Aβ49 and Aβ50, have been qualitatively described in Alzheimer's disease brains 2 . Similar Aβ species have also been found in transgenic mice that overexpress APP carrying FAD-linked mutations 3 . Further quantitative studies have revealed that Aβ43 is deposited more frequently than Aβ40 in both sporadic Alzheimer's disease (SAD) and FAD [4][5][6][7] .How these Aβ species with different C-terminal ends are generated from the precursor has mainly been investigated by cell biological and biochemical methods. A number of studies 8,9 demonstrated that γ/ε-cleavage by γ-secretase activity controls the fate of the C-terminal end. Aβ43, generated from Aβ49 via Aβ46, is subsequently converted to Aβ40 by γ-secretase whereas Aβ42 is independently generated from Aβ48 via Aβ45. It has also been reported that the FAD-associated I213T mutation in the PSEN1 gene increases the generation of longer Aβ species, such as Aβ43, Aβ45 a...

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Section: Discussionmentioning

confidence: 87%

mentioning

confidence: 88%

Potent amyloidogenicity and pathogenicity of Aβ43

et al. 2011

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“…Recently, A␤ DNA vaccines were developed by using virus vectors (33,34). Although, these vaccines effectively decreased A␤ depositions in the brains of model mice, the possibility of viral replication could not be completely excluded.…”

Section: Discussionmentioning

confidence: 99%

Nonviral Aβ DNA vaccine therapy against Alzheimer’s disease: Long-term effects and safety

Okura

Miyakoshi

Kohyama

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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It was recently demonstrated that amyloid ␤ (A␤) peptide vaccination was effective in reducing the A␤ burden in Alzheimer model mice. However, the clinical trial was halted because of the development of meningoencephalitis in some patients. To overcome this problem, anti-A␤ antibody therapy and other types of vaccination are now in trial. In this study, we have developed safe and effective nonviral A␤ DNA vaccines against Alzheimer's disease. We administered these vaccines to model (APP23) mice and evaluated A␤ burden reduction. Prophylactic treatments started before A␤ deposition reduced A␤ burden to 15.5% and 38.5% of that found in untreated mice at 7 and 18 months of age, respectively. Therapeutic treatment started after A␤ deposition reduced A␤ burden toϷ50% at the age of 18 months. Importantly, this therapy induced neither neuroinflammation nor T cell responses to A␤ peptide in both APP23 and wild-type B6 mice, even after long-term vaccination. Although it is reported that other anti-A␤ therapies have pharmacological and͞or technical difficulties, nonviral DNA vaccines are highly secure and easily controllable and are promising for the treatment of Alzheimer's disease. (4) and the passive transfer of anti-A␤ antibodies were also effective in reducing amyloid deposits (5). Moreover, vaccinated mice showed an improvement in memory loss (6, 7). Thus, A␤ peptide vaccine therapy has been shown to be effective in animal models, and human clinical trials were started with Betabloc (AN-1792), composed of synthetic A␤1-42 and QS21 as an adjuvant (8). However, the phase II clinical trial was halted because of the development of acute meningoencephalitis that appeared in 18 (6%) of 298 vaccinated patients (9). Importantly, it was later demonstrated by autopsy that there was a significant reduction of amyloid deposition and disappearance of degenerative axons in a treated patient (10). At the same time, T cell-dominant meningeal encephalitis was present in the cerebral cortex. These findings suggest that the vaccine therapy is a promising strategy for human Alzheimer's disease if excessive immune reactions are minimized to avoid unwanted neuroinflammation.Recently, it was reported that naked plasmid DNAs encoding proteins are taken into cells and produce the proteins in a small amount for a relatively long period when injected into the muscle or skin (11). Then, the proteins that are released in the extracellular space induce antibodies against the proteins (12, 13). Thus, gentle and quiet immune reactions could be obtained by DNA vaccine administration. In our and other's laboratories, immune therapies with DNA vaccines have been examined in autoimmune disease models (14-17) and have been found to be effective in preventing the diseases without the use of adjuvants. Here, we developed nonviral A␤ DNA vaccines and were able to reduce the amyloid burden in the cerebral cortex and hippocampus of Alzheimer's disease model (APP23) mice by vaccination. Importantly, the side effects, such as T cell proliferation and neuroin...

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“…1) AAV-Aβ 1-43 or 1-21 Oral (Hara et al 2004;Mouri et al 2007) 2) AAV-Aβ 1-42 -CTB Oral (Zhang et al 2003) 3) SeV-Aβ 1-43 -IL-10 Nasal (Hara et al in preparation) 4) pCA-PEDI-11 × (Aβ 1-16) boosted with rAV-PEDI*-11 × (Aβ 1-16) Nasal (Kim et al 2007a(Kim et al , 2007b 5) pHSV-Aβ 1-42-IL-4 S.C. (Frazer et al 2008) AAV, adeno-associated virus vector; AV, adenovirus vector; CTB, cholera toxin B; pCA, a plasmid; pHSV, herpes simplex virus amplicon; SeV, Sendai virus vector; PEDI, receptor binding domain of Pseudomonas exotoxin A.…”

Section: Peptide Vaccines a Short N-terminal Aβ Peptide With A Non-enmentioning

confidence: 99%

“…Recombinant Adeno-associated Virus vector (AAV) carrying Aβ 1-43 or Aβ 1-21: We developed recombinant AAV carrying an APP signal sequence and Aβ 1-43 or Aβ 1-21 cDNA (Hara et al 2004). We used Aβ 1-43 in order to differentiate it from native Aβ , because majority of native Aβ is composed of Aβ 40 and Aβ 42.…”

Section: Recombinant Viral Vectorsmentioning

confidence: 99%

Development of a safe oral Aβ vaccine using recombinant adeno-associated virus vector for Alzheimer's disease

Cited by 85 publications

References 20 publications

Potent amyloidogenicity and pathogenicity of Aβ43

Potent amyloidogenicity and pathogenicity of Aβ43

Nonviral Aβ DNA vaccine therapy against Alzheimer’s disease: Long-term effects and safety

Immunization Therapy for Alzheimer Disease: A Comprehensive Review of Active Immunization Strategies

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