P4-358 In vitro and in vivo characterization of beta-amyloid antibodies binding to cerebral amyloid angiopathy (CAA) and the selective exacerbation of CAA-associated microhemorrhage

DeMattos, Ronald B.; Boone, Laura; Hepburn, Deena L.; Parsadanian, Maia; Bryan, Matthew T.; Ness, Daniel; Piroozi, Kathy S.; Holtzman, David M.; Bales, Kelly R.; Gitter, Bruce D.; Paul, Steven M.; Racke, Margaret M.

doi:10.1016/s0197-4580(04)81916-x

Cited by 7 publications

(6 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The sites of microhemorrhage have been co-localized with cerebral vascular Aβ deposits. Similar results were obtained in different strains of APP Tg mice [27,29,30]. Only later was it reported that active immunizations of APP/Tg mice with fibrillar Aβ 42 formulated in a strong conventional adjuvant (CFA/IFA) could also increase microhemorrhages in the brains of vaccinated animals [31].…”

Section: Aβ Immunotherapysupporting

confidence: 69%

Rationale for Peptide and DNA Based Epitope Vaccines for Alzheimers Disease Immunotherapy

Ghochikyan

2009

CNSNDDT

View full text Add to dashboard Cite

Amyloid-beta (Aβ) immunotherapy has received considerable attention as a promising approach for reducing the level of Aβ in the CNS of Alzheimer’s disease patients. However, the first Phase II clinical trial, for the immune therapy AN1792, was halted when a subset of those immunized with Aβ42 developed adverse events in the central nervous system. In addition, data from the trial indicated that there was a low percentage of responders and generally low to moderate titers in the patients mat received the vaccine. Generated antibodies reduced β-amyloid deposits in the parenchyma of patients’ brains, but no reduction in soluble Aβ or significant improvements in cognitive function of patients were observed. These data and data from pre-clinical studies suggest that reduction in the most toxic oligomeric forms of Aβ is important for prevention or slowing down of the progression of cognitive decline, and that vaccination should be started prior to irreversible accumulation of the oligomeric Aβ, at the early stages of AD. Protective immunotherapy requires a development of safe and effective strategy for Aβ immunotherapy. In this review, the rationale for developing epitope vaccines for the treatment of AD will be discussed. We believe that an epitope vaccine will induce an adequate anti-Aβ antibody response in the absence of potentially adverse self T cell-mediated events, making it possible to start immunization at the early stages of AD.

show abstract

Section: Aβ Immunotherapysupporting

confidence: 69%

Rationale for Peptide and DNA Based Epitope Vaccines for Alzheimers Disease Immunotherapy

Ghochikyan

2009

CNSNDDT

View full text Add to dashboard Cite

show abstract

“…More recently, DeMattos et al . [30] showed that passive immunization with an N-terminal antibody (3D6: directed against amino acids 1–5 of Aβ) of PDAPP transgenic mice also resulted in significantly increased microhemorrhage. They were unable to detect increased microhemorrhage with a mid-domain antibody (266: directed against amino acids 13–28 of Aβ).…”

Section: Discussionmentioning

confidence: 99%

Untitled

Wilcock

Rojiani

Rosenthal

et al. 2004

J Neuroinflammation

339

110

View full text Add to dashboard Cite

BackgroundAnti-Aβ immunotherapy in transgenic mice reduces both diffuse and compact amyloid deposits, improves memory function and clears early-stage phospho-tau aggregates. As most Alzheimer disease cases occur well past midlife, the current study examined adoptive transfer of anti-Aβ antibodies to 19- and 23-month old APP-transgenic mice.MethodsWe investigated the effects of weekly anti-Aβ antibody treatment on radial-arm water-maze performance, parenchymal and vascular amyloid loads, and the presence of microhemorrhage in the brain. 19-month-old mice were treated for 1, 2 or 3 months while 23-month-old mice were treated for 5 months. Only the 23-month-old mice were subject to radial-arm water-maze testing.ResultsAfter 3 months of weekly injections, this passive immunization protocol completely reversed learning and memory deficits in these mice, a benefit that was undiminished after 5 months of treatment. Dramatic reductions of diffuse Aβ immunostaining and parenchymal Congophilic amyloid deposits were observed after five months, indicating that even well-established amyloid deposits are susceptible to immunotherapy. However, cerebral amyloid angiopathy increased substantially with immunotherapy, and some deposits were associated with microhemorrhage. Reanalysis of results collected from an earlier time-course study demonstrated that these increases in vascular deposits were dependent on the duration of immunotherapy.ConclusionsThe cognitive benefits of passive immunotherapy persist in spite of the presence of vascular amyloid and small hemorrhages. These data suggest that clinical trials evaluating such treatments will require precautions to minimize potential adverse events associated with microhemorrhage.

show abstract

“…The only adverse event observed was the increased incidence of cerebral hemorrhage detected in very old hemorrhage-prone APP/Tg-23 mice injected with high levels of an anti-Aβ monoclonal antibody [24]. More recently, it was demonstrated that passive immunization with anti-Aβ antibodies directed to aa 1-5, also resulted in significantly increased microhemorrhage [25]. There were no documented reports of APP/Tg models developing cerebral hemorrhages in response to active immunization, however.…”

Section: Immunotherapy For Ad Using Aβ 42 Vaccine: Lessons From Pre-cmentioning

confidence: 99%

“…In contrast, Alum, CFA, and TMG induced only a low-level antibody response against peptide Aβ [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] . No antibodies that recognized the remaining four overlapping linear peptides spanning aa 11-42 (Aβ 11-25 , Aβ [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] , Aβ 21-35 , Aβ 26-42 ) derived from Aβ 42 , were detected (Fig. 3a).…”

Section: B Cell Epitope/s Of Aβ 42mentioning

confidence: 99%

“…Incorporation of a promiscuous foreign T cell epitope into Aβ-immunogen provides a number of significant advantages to Aβ-immunotherapy design. We have selected PADRE (aK-ChaTo map T helper responses to Aβ 42 , we stimulated immune BALB/c splenocytes with Aβ 1-28 (aa 1-28 of Aβ 42 ) or six overlapping small peptides Aβ 1-15 , Aβ 6-20 , Aβ 11-25 , Aβ [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] , Aβ [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] , and Aβ 26-42 derived from Aβ 42 . Only T cells activated in vitro with peptides Aβ 6-20 , Aβ 1-28, or Aβ 1-40 exhibited significant T cell proliferation.…”

Section: Testing Of a Prototype Epitope Vaccine In Micementioning

confidence: 99%

See 1 more Smart Citation

Immunotherapy for Alzheimers Disease: Potential Problems and Possible Solutions

Agadjanyan¹

2005

CIR

View full text Add to dashboard Cite

The primary component of senile plaques is the β-amyloid peptide (Aβ), and the amyloid cascade hypothesis proposes that this putative neuropathological peptide is a causal factor in the onset and progression of Alzheimer's disease (AD). Many of the strategies currently being investigated as therapies for AD are aimed at reducing the level of Aβ in the brain or blocking the assembly of the peptide into potentially pathological forms. Immunization of APP/Tg mice with fibrillar Aβ, induced anti-Aβ antibodies, which reduced Aβ plaque deposition and neuritic dystrophy, astrogliosis in the brains of APP/Tg mice, and diminished learning deficits in these mice. The first clinical trial was halted, however, when 6% of the participants developed some degree of meningoencephalitis. Preliminary analysis of the first clinical trial has produced some encouraging results including a reduction in plaque load and attenuation of cognitive decline in some vaccinated patients. In this review, we discuss the current status of Aβ-immunotherapy and offer our analysis of the probable cause of the failure of the clinical trial. We believe that the development of safe and effective Aβ-immunotherapy requires selection of an antigen that will induce an adequate anti-Aβ antibody response in the absence of potentially adverse self T cell-mediated events.

show abstract

P4-358 In vitro and in vivo characterization of beta-amyloid antibodies binding to cerebral amyloid angiopathy (CAA) and the selective exacerbation of CAA-associated microhemorrhage

Cited by 7 publications

References 0 publications

Rationale for Peptide and DNA Based Epitope Vaccines for Alzheimers Disease Immunotherapy

Rationale for Peptide and DNA Based Epitope Vaccines for Alzheimers Disease Immunotherapy

Untitled

Immunotherapy for Alzheimers Disease: Potential Problems and Possible Solutions

Contact Info

Product

Resources

About