Differential effects of apoE and apoJ mimetic peptides on the action of an anti-Aβ scFv in 3xTg-AD mice

Montoliu‐Gaya, Laia; Güell-Bosch, Jofre; Esquerda-Canals, Gisela; Roda, Alejandro R; Serra-Mir, Gabriel; Lope–Piedrafita, Silvia; Sánchez-Quesada, José Luís; Villegas, Sandra

doi:10.1016/j.bcp.2018.07.012

Cited by 19 publications

(23 citation statements)

References 67 publications

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“…Indeed, the 6E10 immunoreactive area tended to be reduced in scFv-h3D6-treated mice ( t = 1.932, p = 0.0738) ( Figure 7 C). This is in consonance with the extensively reported ability of scFv-h3D6 to reduce Aβ burden in the 3xTg-AD mouse model [ 32 , 33 , 34 , 35 , 43 , 55 ], which is behind the improvement in cognitive functions after treatment. Regarding tau pathology, even though significance was not achieved, a slight reduction in HT7 immunoreactive area could qualitatively be observed ( Figure 7 D).…”

Section: Resultssupporting

confidence: 87%

Cognitive Impairment in the 3xTg-AD Mouse Model of Alzheimer’s Disease is Affected by Aβ-ImmunoTherapy and Cognitive Stimulation

et al. 2020

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Clinical symptoms of Alzheimer’s Disease (AD) include behavioral alterations and cognitive impairment. These functional phenotypes early occur in triple-transgenic (3xTg-AD) mice. Specifically, behavioral alterations are first detected when mice are at around 2.5 months old and cognitive impairment in between 3- and 5-month-old mice. In this work, the effect of chronic Aβ-immunotherapy on behavioral and cognitive abilities was tested by monthly administering the antibody fragment scFv-h3D6 to 3xTg-AD female mice from 5 to 9 months of age. An untreated group was used as a reference, as well as to attain some information on the effect of training during the longitudinal study. Behavioral and psychological symptoms of dementia (BPSD)-like symptoms were already evident in 5-month-old mice, in the form of neophobia and anxious-like behavior. The exploratory activity decreased over the longitudinal study, not only for 3xTgAD mice but also for the corresponding non-transgenic mice (NTg). Learning abilities of 3xTg-AD mice were not seriously compromised but an impairment in long-term spatial memory was evident at 5 months of age. Interestingly, scFv-h3D6-treatment affected the cognitive impairment displayed by 5-month-old 3xTg-AD mice. It is worth noting that training also reduced cognitive impairment of 3xTg-AD mice over the longitudinal study, suggesting that to properly quantify the isolated therapeutic potential of any drug on cognition using this model it is convenient to perform a prompt, age-matched study rather than a longitudinal study. In addition, a combination of both training and Aβ-immunotherapy could constitute a possible approach to treat Alzheimer’s disease.

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Section: Resultssupporting

confidence: 87%

Cognitive Impairment in the 3xTg-AD Mouse Model of Alzheimer’s Disease is Affected by Aβ-ImmunoTherapy and Cognitive Stimulation

et al. 2020

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“…In a recent paper by our group, an evident trend of brain volume reduction was shown in the 3xTg‐AD at 6‐mo, and here it was also observed at 5‐mo. Whole brain and ventricle atrophy has been previously reported in 15‐mo 3xTg‐AD mice while other studies at the same age could not detect brain volume differences .…”

Section: Discussionsupporting

confidence: 84%

“…The triple transgenic mouse model (3xTg‐AD) is extensively used in AD research and reproduces both amyloid and tau pathologies in a regional and temporal pattern analogous to AD patients, which makes it very valuable for longitudinal studies . In vivo magnetic resonance imaging (MRI) and proton spectroscopy ( 1 H‐MRS) have recently begun to be used for the characterization of the triple transgenic Alzheimer's Disease mouse model . MRI not only provides structural information but also relevant functional evidence when acquiring multiparametric MRI maps.…”

Section: Introductionmentioning

confidence: 99%

Progression of Alzheimer's disease and effect of scFv‐h3D6 immunotherapy in the 3xTg‐AD mouse model: An in vivo longitudinal study using Magnetic Resonance Imaging and Spectroscopy

et al. 2020

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Alzheimer's disease (AD) is an incurable disease that affects most of the 47 million people estimated as living with dementia worldwide. The main histopathological hallmarks of AD are extracellular β-amyloid (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein.In recent years, Aβ-immunotherapy has been revealed as a potential tool in AD treatment. One strategy consists of using single-chain variable fragments (scFvs), which avoids the fragment crystallizable (Fc) effects that are supposed to trigger a microglial response, leading to microhemorrhages and vasogenic edemas, as evidenced in clinical trials with bapineuzumab. The scFv-h3D6 generated by our research group derives from this monoclonal antibody, which targets the N-terminal of the Aβ peptide and recognizes monomers, oligomers and fibrils.In this study, 3xTg-AD mice were intraperitoneally and monthly treated with 100 μg of scFv-h3D6 (a dose of~3.3 mg/kg) or PBS, from 5 to 12 months of age (−mo), the age at which the mice were sacrificed and samples collected for histological and biochemical analyses. During treatments, four monitoring sessions using magnetic resonance imaging and spectroscopy (MRI/MRS) were performed at 5, 7, 9, and 12 months of age. MRI/MRS techniques are widely used in both human and mouse research, allowing to draw an in vivo picture of concrete aspects of the pathology in a non-invasive manner and allowing to monitor its development across time.Compared with the genetic background, 3xTg-AD mice presented a smaller volume in almost all cerebral regions and ages examined, an increase in both the intra and extracellular Aβ 1-42 at 12-mo, and an inflammation process at this age, in both the hippocampus (IL-6 and mIns) and cortex (IL-6). In addition, treatment with scFv-h3D6 partially recovered the values in brain volume, and Aβ, IL-6, and mIns concentrations, among others, encouraging further studies with this antibody fragment.Abbreviations: 3xTg-AD, triple-transgenic mouse model of AD.; 6E10+, mAb-6E10 immunoreactive

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“…At this initial point in the discussion, an important methodological issue is worth mentioning. As we [18,[21][22][23][24][25] and other authors [39][40][41][42] have extensively argued, although 6E10 mAb is able to recognize Aβ, β-CTD, and APP, what we are measuring in the 3xTg-AD mouse with this mAb is nowadays agreed to be the Aβ peptide. The present work constitutes another demonstration of this fact since scFv-h3D6, which exclusively recognizes the Aβ peptide, promotes a comparable decrease in both 6E10-labeling and Aβ40-and Aβ42-specific signals by ELISA.…”

Section: Discussionmentioning

confidence: 73%

“…We have previously reported that scFv-h3D6 reduces extracellular Aβ oligomers [21] and intracellular Aβ levels [22] after a single intraperitoneal dose to 5-month-old 3xTg-AD mice. We could also observe these effects after treatment for 6 weeks to a similar group of animals [23]. However, the effect of the scFv-h3D6 in elderly animals with an advanced stage of AD-like pathology, where plaques are present, has not yet been evaluated.…”

Section: Scfv-h3d6 Reduces the Area Of 6e10 Stainingmentioning

confidence: 93%

Both Amyloid-β Peptide and Tau Protein Are Affected by an Anti-Amyloid-β Antibody Fragment in Elderly 3xTg-AD Mice

Roda

Montoliu‐Gaya

Serra-Mir

et al. 2020

IJMS

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Alzheimer’s disease (AD) is the most common dementia worldwide. According to the amyloid hypothesis, the early accumulation of the Aβ-peptide triggers tau phosphorylation, synaptic dysfunction, and eventually neuronal death leading to cognitive impairment, as well as behavioral and psychological symptoms of dementia. ScFv-h3D6 is a single-chain variable fragment that has already shown its ability to diminish the amyloid burden in 5-month-old 3xTg-AD mice. However, tau pathology is not evident at this early stage of the disease in this mouse model. In this study, the effects of scFv-h3D6 on Aβ and tau pathologies have been assessed in 22-month-old 3xTg-AD mice. Briefly, 3xTg-AD female mice were treated for 2 weeks with scFv-h3D6 and compared with 3xTg-AD and non-transgenic (NTg) mice treated with PBS. The treatment with scFv-h3D6 was unequivocally effective in reducing the area of Aβ staining. Furthermore, a tendency for a reduction in tau levels was also observed after treatment that points to the interplay between Aβ and tau pathologies. The pro-inflammatory state observed in the 3xTg-AD mice did not progress after scFv-h3D6 treatment. In addition, the treatment did not alter the levels of apolipoprotein E or apolipoprotein J. Thus, a 2-week treatment with scFv-h3D6 was able to reduce AD-like pathology in elderly 3xTg-AD female mice.

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Differential effects of apoE and apoJ mimetic peptides on the action of an anti-Aβ scFv in 3xTg-AD mice

Cited by 19 publications

References 67 publications

Cognitive Impairment in the 3xTg-AD Mouse Model of Alzheimer’s Disease is Affected by Aβ-ImmunoTherapy and Cognitive Stimulation

Cognitive Impairment in the 3xTg-AD Mouse Model of Alzheimer’s Disease is Affected by Aβ-ImmunoTherapy and Cognitive Stimulation

Progression of Alzheimer's disease and effect of scFv‐h3D6 immunotherapy in the 3xTg‐AD mouse model: An in vivo longitudinal study using Magnetic Resonance Imaging and Spectroscopy

Both Amyloid-β Peptide and Tau Protein Are Affected by an Anti-Amyloid-β Antibody Fragment in Elderly 3xTg-AD Mice

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