Species-specific immune response to immunization with human versus rodent Aβ peptide

Seabrook, Timothy J.; Bloom, Jerry; Iglesias, Melitza; Spooner, E. T. C.; Walsh, Dominic M.; Lemere, Cynthia A.

doi:10.1016/j.neurobiolaging.2003.12.008

Cited by 24 publications

(18 citation statements)

References 44 publications

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“…Nonetheless, we studied animals of the J20 strain that were older than 11 months of age and did not observe substantial increases in Aβ deposition linked to age in the cohort we studied (Aβ deposition values as determined both by ELISA and thioflavin S staining for individual mice in each treatment group and controls are presented in Supplemental Tables 1-3; supplemental material available online with this article; doi:10.1172/JCI23241DS1). Our experience is consistent with the reports of other investigators who did not find a large increase in Aβ levels in animals between the ages of 12 and 15 months (32)(33)(34). Also, when we exactly age-matched our control group (13.3 months) with MOG-EAE animals and animals treated nasally with GA+IVX-908, we found a significant effect of treatment on Aβ levels measured by 2 methods (P < 0.001; Supplemental Table 4).…”

Section: Figuresupporting

confidence: 92%

Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears β-amyloid in a mouse model of Alzheimer disease

Frenkel¹,

Maron²,

Burt³

et al. 2005

J. Clin. Invest.

163

115

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Amyloid β-peptide (Aβ) appears to play a key pathogenic role in Alzheimer disease (AD). Immune therapy in mouse models of AD via Aβ immunization or passive administration of Aβ antibodies markedly reduces Aβ levels and reverses behavioral impairment. However, a human trial of Aβ immunization led to meningoencephalitis in some patients and was discontinued. Here we show that nasal vaccination with a proteosome-based adjuvant that is well tolerated in humans plus glatiramer acetate, an FDA-approved synthetic copolymer used to treat multiple sclerosis, potently decreases Aβ plaques in an AD mouse model. This effect did not require the presence of antibody, as it was observed in B cell-deficient (Ig m-null) mice. Vaccinated animals developed activated microglia that colocalized with Aβ fibrils, and the extent of microglial activation correlated strongly with the decrease in Aβ fibrils. Activation of microglia and clearing of Aβ occurred with the adjuvant alone, although to a lesser degree. Our results identify a novel approach to immune therapy for AD that involves clearing of Aβ through the utilization of compounds that have been safely tested on or are currently in use in humans. IntroductionAlzheimer disease (AD) is the most common form of senile dementia, affecting more than 18 million people worldwide. With increased life expectancy, this number is expected to rise in the future. AD is characterized by widespread functional disturbance of the human brain. The classical neuropathological features are senile plaques, neurofibrillary tangles composed of paired helical filaments, and dystrophic neuritis. Compact senile plaques composed of amyloid β-peptide (Aβ) fibrils are associated with pathological changes in the surrounding brain neurons that lead to their death. Aβ appears to play a key pathogenic role in AD (1), and studies have connected the Aβ plaque with formation of intracellular tau tangles, another neurotoxic feature of AD (2, 3).A body of work has accumulated demonstrating that anti-Aβ antibodies are effective in clearance of amyloid deposits in vitro and in amyloid precursor protein-Tg (APP-Tg) mice (4-10). Solomon et al. showed in vitro that anti-Aβ antibodies can lead to disaggregation of Aβ fibrils, restoring Aβ solubility and thus prevent neurotoxic effects on cell lines (11, 12). Schenk et al. then demonstrated that parenteral immunization of APP-Tg mice with synthetic Aβ in complete Freund adjuvant (CFA) markedly decreased the number and density of Aβ deposits in the brain, with concomitant

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Section: Figuresupporting

confidence: 92%

Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears β-amyloid in a mouse model of Alzheimer disease

Frenkel¹,

Maron²,

Burt³

et al. 2005

J. Clin. Invest.

163

115

View full text Add to dashboard Cite

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“…As expected, control treated APP+PS1 mice as well as mice receiving only NCX-2216 demonstrated no anti-Aβ antibody titers. These titers (approximately 8 μg/ml) are low compared to results reported by others after inoculations in active immunization protocols (Seabrook et al, 2004;Das et al, 2003). This may reflect the advanced age of the mice at sacrifice (20 mo), the variations between laboratories in the ELISA protocol used to measure the antibody titers or the 2 month interval from the last inoculation.…”

Section: Resultsmentioning

confidence: 55%

Amyloid-β vaccination, but not nitro-nonsteroidal anti-inflammatory drug treatment, increases vascular amyloid and microhemorrhage while both reduce parenchymal amyloid

Wilcock¹,

Jantzen²,

Li³

et al. 2007

Neuroscience

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Vaccination with Aβ 1-42 and treatment with NCX-2216, a novel nitric oxide releasing flurbiprofen derivative, have each been shown separately to reduce amyloid deposition in transgenic mice and have been suggested as potential therapies for Alzheimer's disease. In the current study we treated doubly transgenic amyloid precursor protein and presenilin-1 (APP+PS1) mice with Aβ 1-42 vaccination, NCX-2216 or both drugs simultaneously for 9 months. We found that all treatments reduced amyloid deposition, both compact and diffuse, to the same extent while only vaccinated animals, with or without non-steroidal anti-inflammatory drug (NSAID) treatment, showed increased microglial activation associated with the remaining amyloid deposits. We also found that active Aβ vaccination resulted in significantly increased cerebral amyloid angiopathy and associated microhemorrhages, while NCX-2216 did not, in spite of similar reductions in parenchymal amyloid. Co-administration of NCX-2216 did not attenuate this effect of the vaccine. This is the first report showing that active immunization can result in increased vascular amyloid and microhemorrhage, as has been observed with passive immunization. Co-administration of an NSAID agent with Aβ vaccination does not substantially modify the effects of Aβ immunotherapy. The difference between these treatments with respect to vascular amyloid development may reflect the clearance-promoting actions of the vaccine as opposed to the production-modifying effects proposed for flurbiprofen.

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“…This difference was best discerned when low titers of the antimouse IgG-HRP were used. Seabrook et al (2004) also reported immunohistochemical labeling of amyloid deposits for mouse IgG after passive immunization but detected signals in both immunized and nonimmunized mice. It is unclear whether lower anti-mouse IgG concentrations might have revealed selective staining in anti-A␤-treated animals.…”

Section: Discussionmentioning

confidence: 97%

Passive Amyloid Immunotherapy Clears Amyloid and Transiently Activates Microglia in a Transgenic Mouse Model of Amyloid Deposition

Wilcock¹,

Rojiani²,

Rosenthal³

et al. 2004

J. Neurosci.

282

248

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The role of microglia in the removal of amyloid deposits after systemically administered anti-A␤ antibodies remains unclear. In the current study, we injected Tg2576 APP transgenic mice weekly with an anti-A␤ antibody for 1, 2, or 3 months such that all mice were 22 months at the end of the study. In mice immunized for 3 months, we found an improvement in alternation performance in the Y maze. Histologically, we were able to detect mouse IgG bound to congophilic amyloid deposits in those mice treated with the anti-A␤ antibody but not in those treated with a control antibody. We found that Fc␥ receptor expression on microglia was increased after 1 month of treatment, whereas CD45 was increased after 2 months of treatment. Associated with these microglial changes was a reduction in both diffuse and compact amyloid deposits after 2 months of treatment. Interestingly, the microglia markers were reduced to control levels after 3 months of treatment, whereas amyloid levels remained reduced. Serum A␤ levels and anti-A␤ antibody levels were elevated to similar levels at all three survival times in mice given anti-A␤ injections rather than control antibody injections. These data show that the antibody is able to enter the brain and bind to the amyloid deposits, likely opsonizing the A␤ and resulting in Fc␥ receptor-mediated phagocytosis. Together with our earlier work, our data argue that all proposed mechanisms of anti-A␤ antibody-mediated amyloid removal can be simultaneously active.

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Species-specific immune response to immunization with human versus rodent Aβ peptide

Cited by 24 publications

References 44 publications

Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears β-amyloid in a mouse model of Alzheimer disease

Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears β-amyloid in a mouse model of Alzheimer disease

Amyloid-β vaccination, but not nitro-nonsteroidal anti-inflammatory drug treatment, increases vascular amyloid and microhemorrhage while both reduce parenchymal amyloid

Passive Amyloid Immunotherapy Clears Amyloid and Transiently Activates Microglia in a Transgenic Mouse Model of Amyloid Deposition

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