Number of A<i>β</i> Inoculations in APP+PS1 Transgenic Mice Influences Antibody Titers, Microglial Activation, and Congophilic Plaque Levels

Wilcock, Donna M.; Gordon, Marcia N.; Ugen, Kenneth E.; Gottschall, Paul E.; DiCarlo, Giovanni; Dickey, Chad A.; Boyett, Kristal W.; Jantzen, Paul T.; Connor, Karen E.; Melachrino, Jason; Hardy, John; Morgan, David

doi:10.1089/10445490152717596

Cited by 86 publications

(65 citation statements)

References 20 publications

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“…It has also been shown to attenuate memory loss in APP+PS1 transgenic mice (Morgan et al, 2000) and in singly transgenic APP mice (Janus et al, 2000). We have also shown that there appears to be a dependence on microglial activation for the removal of compact, Congophilic amyloid deposits following active vaccination (Wilcock et al, 2001) and following direct intracranial injection of anti-Aβ antibodies (Wilcock et al, 2003). In the current study we show that Aβ vaccination results in generation of significant anti-Aβ antibody titers, reduced amyloid deposition and increased microglial activation associated with the remaining compact amyloid deposits.…”

Section: Discussionmentioning

confidence: 66%

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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Section: Discussionmentioning

confidence: 66%

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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“…These include the prevention of neurotoxic fibril formation (27), efflux of soluble A␤ from the brain to the plasma, also known as the peripheral sink mechanism (32), and microglia-mediated removal of A␤ (1,7,34,35,41). Results from our study indicate that all three mechanisms may be at work.…”

Section: Discussionmentioning

confidence: 70%

Papillomavirus-Like Particles Are an Effective Platform for Amyloid-β Immunization in Rabbits and Transgenic Mice

Zamora

Handisurya

Shafti-Keramat

et al. 2006

The Journal of Immunology

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Immunization with amyloid-β (Aβ) prevents the deposition of Aβ in the brain and memory deficits in transgenic mouse models of Alzheimer’s disease (AD), opening the possibility for immunotherapy of AD in humans. Unfortunately, the first human trial of Aβ vaccination was complicated, in a small number of vaccinees, by cell-mediated meningoencephalitis. To develop an Aβ vaccine that lacks the potential to induce autoimmune encephalitis, we have generated papillomavirus-like particles (VLP) that display 1–9 aa of Aβ protein repetitively on the viral capsid surface (Aβ-VLP). This Aβ peptide was chosen because it contains a functional B cell epitope, but lacks known T cell epitopes. Rabbit and mouse vaccinations with Aβ-VLP were well tolerated and induced high-titer autoAb against Aβ, that inhibited effectively assembly of Aβ1–42 peptides into neurotoxic fibrils in vitro. Following Aβ-VLP immunizations of APP/presenilin 1 transgenic mice, a model for human AD, we observed trends for reduced Aβ deposits in the brain and increased numbers of activated microglia. Furthermore, Aβ-VLP vaccinated mice also showed increased levels of Aβ in plasma, suggesting efflux from the brain into the vascular compartment. These results indicate that the Aβ-VLP vaccine induces an effective humoral immune response to Aβ and may thus form a basis to develop a safe and efficient immunotherapy for human AD.

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“…CD45 is a tyrosine phosphatase that plays critical roles in immune receptor signaling. CD45 expression levels are elevated in reactive microglia in the AD brain (Masliah et al, 1991) and in murine models of the disease (Wilcock et al, 2001). We also found that there was an ibuprofen-mediated 49% reduction ( p Ͻ 0.05) in the expression of the complement receptor 3 subunit CD11b (Fig.…”

Section: Resultsmentioning

confidence: 99%

Anti-Inflammatory Drug Therapy Alters β-Amyloid Processing and Deposition in an Animal Model of Alzheimer's Disease

et al. 2003

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Alzheimer's disease (AD) is characterized by a microglial-mediated inflammatory response elicited by extensive amyloid deposition in the brain. Nonsteroidal anti-inflammatory drug (NSAID) treatment reduces AD risk, slows disease progression, and reduces microglial activation; however, the basis of these effects is unknown. We report that treatment of 11-month-old Tg2576 mice overexpressing human amyloid precursor protein (APP) with the NSAID ibuprofen for 16 weeks resulted in the dramatic and selective reduction of SDS-soluble ␤-amyloid (A␤) 42 , whereas it had smaller effects on SDS-soluble A␤ 40 levels. Ibuprofen treatment resulted in 60% reduction of amyloid plaque load in the cortex of these animals. In vitro studies using APP-expressing 293 cells showed that ibuprofen directly affected APP processing, specifically reducing the production of A␤ 42 . Ibuprofen treatment resulted in a significant reduction in microglial activation in the Tg2576 mice, as measured by CD45 and CD11b expression. NSAIDs activate the nuclear hormone receptor peroxisome proliferatoractivated receptor ␥ (PPAR␥); however, a potent agonist of this receptor, pioglitazone, only modestly reduced SDS-soluble A␤ levels and did not affect amyloid plaque burden or microglia activation, indicating that PPAR␥ activation is not involved in the A␤ lowering effect of NSAIDs. These data show that chronic NSAID treatment can reduce brain A␤ levels, amyloid plaque burden, and microglial activation in an animal model of Alzheimer's disease.

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Number of Aβ Inoculations in APP+PS1 Transgenic Mice Influences Antibody Titers, Microglial Activation, and Congophilic Plaque Levels

Cited by 86 publications

References 20 publications

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

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

Papillomavirus-Like Particles Are an Effective Platform for Amyloid-β Immunization in Rabbits and Transgenic Mice

Anti-Inflammatory Drug Therapy Alters β-Amyloid Processing and Deposition in an Animal Model of Alzheimer's Disease

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