Alzheimer's Disease Peptide Epitope Vaccine Reduces Insoluble But Not Soluble/Oligomeric Aβ Species in Amyloid Precursor Protein Transgenic Mice

Petrushina, Irina; Ghochikyan, Anahit; Mktrichyan, Mikayel; Mamikonyan, Grigor; Movsesyan, Nina; Davtyan, Hayk; Patel, Samir; Head, Elizabeth; Cribbs, David H.; Agadjanyan, Michael G.

doi:10.1523/jneurosci.3201-07.2007

Cited by 87 publications

(113 citation statements)

References 64 publications

(109 reference statements)

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“…40,[65][66][67][68] Importantly, immunizations of mouse models of AD with EV induced therapeutically potent antiAb antibodies that inhibited accumulation of AD-like plaque pathology in the brains of older mice, reduced glial activation, and prevented the development of behavioral deficits in aged animals without increasing the incidence of microhemorrhages. 40,42,43 In this study, we decided to compare the efficacy of our EV strategy in preventive and therapeutic settings in parallel. Results from these combined www.moleculartherapy.org studies demonstrated that the preventive, but not therapeutic, vaccination strategy was effective in reduction of AD-like pathology in the brains of aged Tg2576 mice (Figures 2, 3A, and 3B) without increasing the incidence of microhemorrhages and CAA ( Figures 3C and 3D).…”

Section: Discussionmentioning

confidence: 99%

“…40,42,43 In this study, we decided to compare the efficacy of EV targeting the N terminus of Ab in preventive and therapeutic settings in parallel. More specifically, we started immunizations of Tg2576 mice at a time when they possessed low (at 6-6.5 months old) and high (at 16-19 months old) levels of AD-like pathology, respectively ( Figures 1A and 1B).…”

Section: Comparison Of Efficacy Of Preventive and Therapeutic Evmentioning

confidence: 99%

“…40,43,65,66 Anti-Ab antibody concentrations in mice were calculated using a calibration curve generated with 6E10 monoclonal antibody (Covance).…”

Section: Experimental Set IImentioning

confidence: 99%

“…Ab cored and defused deposits were detected with 6E10 (1:1000, Covance), as described by Davtyan, Movsesyan, and Petrushina and colleagues. 40,42,43 Activated microglia were stained with the anti-I-A/I-E (marker of MHC II alloantigens, 1:100, BD PharMingen), and astrocytes were labeled with anti-GFAP (glial fibriliary acidic protein, 1:500, Dako) antibody as we described. 40,42,43 Fibrillar Ab deposits were visualized using Thioflavin S (ThS; Sigma-Aldrich), and hemosiderin deposits were detected via Prussian Blue staining.…”

Section: Brain Collectionmentioning

confidence: 99%

“…Both assays were performed as described by Davtyan, Movsesyan, and Petrushina and colleagues. 40,42,43 Quantitative Image Analysis…”

Section: Brain Collectionmentioning

confidence: 99%

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Comparison of Efficacy of Preventive and Therapeutic Vaccines Targeting the N Terminus of β-Amyloid in an Animal Model of Alzheimer’s Disease

et al. 2017

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Previously, we reported that Alzheimer's disease (AD) epitope vaccines (EVs) composed of N-terminal b-amyloid (Ab 42 ) B cell epitope fused with universal foreign T helper (Th) epitope(s) were immunogenic, potent, and safe in different amyloid precursor protein (APP) transgenic mice with early AD-like pathology. However, developing an effective therapeutic vaccine is much more challenging, especially when a self-antigen such as Ab 42 is a target. Here, we directly compare the efficacy of anti-Ab 42 antibodies in Tg2576 mice with low or high levels of AD-like pathology at the start of immunizations: 6-6.5 months for preventive vaccinations and 16-19 months for therapeutic vaccinations. EV in a preventive setting induced high levels of anti-Ab antibodies, significantly reducing pathologic forms of Ab in the brains of Tg2576 mice. When used therapeutically for immunesenescent Tg2576 mice, EV induced low levels of antibodies not sufficient for clearing of AD-like pathology. Separately, we demonstrated that EV was also not effective in 11-11.5-month-old Tg2576 mice with moderate AD-like pathology. However, we augmented the titers of anti-Ab antibodies in transgenic (Tg) mice of the same age possessing the pre-existing memory Th cells and detected a significant decrease in diffuse and core plaques in cortical regions compared to control animals along with improved novel object recognition performance. INTRODUCTIONA critical goal of developing therapeutic interventions for Alzheimer's disease (AD) has been the identification of suitable targets. During the last two decades, the predominant theory of the etiology of AD was that Ab has a central role in the onset and progression of AD, as delineated in the amyloid cascade hypothesis. 1,2 According to this hypothesis, the accumulation of Ab peptide, either by overproduction or aberrant clearance, results in deposition of Ab in plaques, which leads to the formation of neurofibrillary tau tangles and cell death, resulting in dementia. Later on, the amyloid cascade hypothesis evolved to focus on oligomers and protofibrils of Ab as instigators in the destruction of synaptic function. [3][4][5] Support for the amyloid cascade hypothesis was spurred by the identification of mutations in amyloid precursor protein (APP) that are associated with familial AD 6-8 or protection against amyloid pathology and age-related Alzheimer's disease. [9][10][11] In addition, it was discovered that overexpression of APP due to trisomy 21 in Downs disease was associated with a high incidence of AD in these individuals. [12][13][14] Today it is clear that the pathological tau also plays a vital role in the development of AD pathology and progression of this disease, 15 correlating better with the degree of dementia than Ab plaques. Importantly, substantial data suggest that Ab pathology emerges many years prior to tau pathology and accelerates formation of toxic tau aggregates, [16][17][18] supporting the preventive rather than therapeutic potential of anti-amyloid therapies.Immunotherapies target...

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Section: Discussionmentioning

confidence: 99%

Section: Comparison Of Efficacy Of Preventive and Therapeutic Evmentioning

confidence: 99%

“…40,43,65,66 Anti-Ab antibody concentrations in mice were calculated using a calibration curve generated with 6E10 monoclonal antibody (Covance).…”

Section: Experimental Set IImentioning

confidence: 99%

Section: Brain Collectionmentioning

confidence: 99%

“…Both assays were performed as described by Davtyan, Movsesyan, and Petrushina and colleagues. 40,42,43 Quantitative Image Analysis…”

Section: Brain Collectionmentioning

confidence: 99%

See 3 more Smart Citations

Comparison of Efficacy of Preventive and Therapeutic Vaccines Targeting the N Terminus of β-Amyloid in an Animal Model of Alzheimer’s Disease

et al. 2017

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The Recent Updates of Therapeutic Approaches Against Aβ for the Treatment of Alzheimer's Disease

Shao

Zhou

Rudd

et al. 2011

The Anatomical Record

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One of the main neuropathological lesions observed in brain autopsy of Alzheimer's disease (AD) patients is the extracellular senile plaques mainly composed of amyloid-beta (Ab) peptide. Recently, treatment strategies have focused on modifying the formation, clearance, and accumulation of this potentially neurotoxic peptide. b-and c-secretase are responsible for the cleavage of amyloid precursor protein (APP) and the generation of Ab peptide. Treatments targeting these two critical secretases may therefore reduce Ab peptide levels and positive impact on AD. Vaccination is also an advanced approach against Ab. This review focuses on recent advances of our understanding of this key peptide, with emphasis on Ab peptide synthesis, accumulation and neurotoxicity, and current therapies including vaccination and two critical secretase inhibitors. MicroRNAs (miRNAs) are a class of conserved endogenous small noncoding RNAs, known to regulate the expression of complementary messenger RNAs, involved in AD development. We therefore address the relationship of miRNAs in the brain and Ab generation, as a novel therapeutic approach to the treatment of AD while also providing new insights on the etiology of this neurological disorder. Anat Rec, 294:1307Rec, 294: -1318Rec, 294: , 2011. V V C 2011 Wiley-Liss, Inc.

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Development of vaccination approaches for the treatment of neurological diseases

Federoff

2009

J of Comparative Neurology

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Several progressive neurodegenerative diseases share a common pathology: the accumulation of misfolded proteins within cells or neuropil of the brain. Characteristically, these misfolded proteins form organized beta-sheet-containing assemblies that have optical and biochemical properties of amyloid. Thus, the brain amyloidoses, Alzheimer's disease (AD), Parkinson's disease, and the prionoses or transmissible spongioform encelphalopathies (TSEs) all manifest putatively pathogenic misfolded proteins, suggesting that these proteins or their precursors may be targets for therapeutics development efforts. Two different biological approaches, both predicated on vaccination, are discussed in this monograph as preclinical approaches for the treatment of AD and a TSE. Herein, I first describe an active vaccination approach that exploits immune shaping to engender a prophylactic T(H)2 response to Abeta in AD mouse models. Second, I describe a passive vaccination strategy whereby recombinant adeno-associated virus vectored delivery of anti-prion single-chain fragment variable antibodies attenuates disease progression and promotes life extension in a mouse TSE model.

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Alzheimer's Disease Peptide Epitope Vaccine Reduces Insoluble But Not Soluble/Oligomeric Aβ Species in Amyloid Precursor Protein Transgenic Mice

Cited by 87 publications

References 64 publications

Comparison of Efficacy of Preventive and Therapeutic Vaccines Targeting the N Terminus of β-Amyloid in an Animal Model of Alzheimer’s Disease

Comparison of Efficacy of Preventive and Therapeutic Vaccines Targeting the N Terminus of β-Amyloid in an Animal Model of Alzheimer’s Disease

The Recent Updates of Therapeutic Approaches Against Aβ for the Treatment of Alzheimer's Disease

Development of vaccination approaches for the treatment of neurological diseases

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