Immunomodulation targeting of both Aβ and tau pathological conformers ameliorates Alzheimer’s disease pathology in TgSwDI and 3xTg mouse models

Goñi, Fernando; Herline, Krystal; Peyser, Daniel; Wong, Kinlung; Ji, Yong; Sun, Yanjie; Mehta, Pankaj; Wısnıewskı, Thomas

doi:10.1186/1742-2094-10-150

Cited by 40 publications

(59 citation statements)

References 63 publications

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“…The solution was neutralized with Tris buffer then dialysed against deionized distilled water overnight and lyophilized. It could be re-solubilized in deionized distilled water and diluted in PBS until required (Goni et al, 2010, 2013). …”

Section: Methodsmentioning

confidence: 99%

Effects of an amyloid-beta 1-42 oligomers antibody screened from a phage display library in APP/PS1 transgenic mice

Wang

et al. 2016

Brain Research

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We screened anti-Aβ1-42 antibodies from a human Alzheimer’s disease (AD) specific single chain variable fragment (scFv) phage display library and assessed their effects in APP/PS1 transgenic mice. Reverse transcription-PCR was used to construct the scFv phage display library, and screening identified 11A5 as an anti-Aβ1-42 antibody. We mixed 11A5 and the monoclonal antibody 6E10 with Aβ1-42 and administered the mixture to Sprague-Dawley rats via intracerebroventricular injection. After 30 days, rats injected with the antibody/ Aβ1-42 mixture and those injected with Aβ1-42 alone were tested on the Morris water maze. We also injected 11A5 and 6E10 into APP/PS1 transgenic mice and assessed the concentrations of Aβ in brain and peripheral blood by ELISA at 1-month intervals for 3 months. Finally we evaluated behavior changes in the Morris water maze. Rats injected with Aβ1-42 and mixed antibodies showed better performance in the Morris water maze than did rats injected with Aβ1-42 alone. In APP/PS1 transgenic mice, Aβ concentration was lower in the brains of the antibody-treated group than in the control group, but higher in the peripheral blood. The antibody-treated mice also exhibited improved behavioral performance in the Morris water maze. In conclusion, anti-Aβ1-42 antibodies (11A5) screened from the human scFv antibody phage display library promoted the efflux or clearance of Aβ1-42 and effectively decreased the cerebral Aβ burden in an AD mouse model.

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Section: Methodsmentioning

confidence: 99%

Effects of an amyloid-beta 1-42 oligomers antibody screened from a phage display library in APP/PS1 transgenic mice

Wang

et al. 2016

Brain Research

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“…The bacterial suspension was centrifuged at 1,200xg for 20 min at 15°C, washed once with sterile saline, centrifuged again and dilute to 1x10 11 colony forming units/ml. The cervid PrP produced by Salmonella LVR01, with a viability of >97%, was tested for sensitivity to proteinase K digestion, using methods previously described [18;20]. …”

Section: Methodsmentioning

confidence: 99%

“…These last 3 vaccinations were supplemented with 100 μg of PK sensitive, polymerized cervid recombinant PrP (provided by DB) also applied to the rumen, tonsil and rectum. The polymerization of the recombinant PrP using glutaraldehyde was done as previously reported [20;23]. Deer were bled prior to the first vaccination (T0), and following the times of vaccination, with T7 being collected prior to oral challenge of all the deer with the CWD agent (on day 323 following the original Salmonella vaccination).…”

Section: Methodsmentioning

confidence: 99%

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Mucosal immunization with an attenuated Salmonella vaccine partially protects white-tailed deer from chronic wasting disease

Goñi

Mathiason

Yim

et al. 2015

Vaccine

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Prion disease is a unique category of illness, affecting both animals and humans, in which the underlying pathogenesis is related to a conformational change of a normal, self-protein called PrPC (C for cellular) to a pathological and infectious conformer known as PrPSc (Sc for scrapie). Bovine spongiform encephalopathy (BSE), a prion disease believed to have arisen from feeding cattle with prion contaminated meat and bone meal products, crossed the species barrier to infect humans. Chronic wasting disease (CWD) infects large numbers of deer and elk, with the potential to infect humans. Currently no prionosis has an effective treatment. Previously, we have demonstrated we could prevent transmission of prions in a proportion of susceptible mice with a mucosal vaccine. In the current study, white-tailed deer were orally inoculated with attenuated Salmonella expressing PrP, while control deer were orally inoculated with vehicle attenuated Salmonella. Once a mucosal response was established, the vaccinated animals were boosted orally and locally by application of polymerized recombinant PrP onto the tonsils and rectal mucosa. The vaccinated and control animals were then challenged orally with CWD-infected brain homogenate. Three years post CWD oral challenge all control deer developed clinical CWD (median survival 602 days), while among the vaccinated there was a significant prolongation of the incubation period (median survival 909 days; p=0.012 by Weibull regression analysis) and one deer has remained CWD free both clinically and by RAMALT and tonsil biopsies. This negative vaccinate has the highest titers of IgA in saliva and systemic IgG against PrP. Western blots showed that immunoglobulins from this vaccinate react to PrPCWD. We document the first partially successful vaccination for a prion disease in a species naturally at risk.

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“…Anti-tau oligomer antibodies which block tau aggregation have also been shown to be effective in P301S Tg mice; however, this study used cranial intra-ventricular injections, limiting its clinical translatability [29]. An additional recent novel approach is the use of active immunization that produces an immune response to both pathological Aβ and tau conformers concurrently; this has been shown to be effective in a number of different AD Tg models [30]. These various preclinical tau pathology directed immunotherapy studies have led to the first Phase I vaccine trial, AADvac1, which uses a pathology related tau peptide conjugated to KLH for active immunization; this trial is on-going (www.clinicaltrials.gov).…”

Section: The Tau Protein and Tau Directed Therapymentioning

confidence: 99%

Tau-Based Therapeutic Approaches for Alzheimer's Disease - A Mini-Review

Boutajangout

Wısnıewskı²

2014

Gerontology

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The accumulation of aggregated, hyperphosphorylated tau as neurofibrillary tangles and neuropil threads are cardinal features of Alzheimer's disease (AD). The other lesions found in AD include amyloid plaques and congophilic amyloid angiopathy, both associated with the extracellular accumulation of the amyloid-beta (Aβ) peptide. AD is the most common cause of dementia globally. Currently, there are no effective means to treat AD or even to slow it down. The dominant theory for the causation of AD is the amyloid cascade hypothesis, which suggests that the aggregation of Aβ as oligomers and amyloid plaques is central to the pathogenesis of AD. Numerous therapies have been developed directed to Aβ-related pathology, in particular various immunotherapeutic approaches. So far all of these have failed in clinical trials. Recently, there has been more focus on therapy directed to tau-related pathology, which correlates better with the cognitive status of patients, compared to the amyloid burden. Immunotherapeutic targeting of tau pathology has shown great potential in treating tau pathologies in mouse models of AD. A number of studies have shown the efficacy of both passive and active immunization. This review summarizes recent advances in therapy targeting pathological tau protein, in particular focusing on immunotherapeutic approaches which are showing great promise.

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Immunomodulation targeting of both Aβ and tau pathological conformers ameliorates Alzheimer’s disease pathology in TgSwDI and 3xTg mouse models

Cited by 40 publications

References 63 publications

Effects of an amyloid-beta 1-42 oligomers antibody screened from a phage display library in APP/PS1 transgenic mice

Effects of an amyloid-beta 1-42 oligomers antibody screened from a phage display library in APP/PS1 transgenic mice

Mucosal immunization with an attenuated Salmonella vaccine partially protects white-tailed deer from chronic wasting disease

Tau-Based Therapeutic Approaches for Alzheimer's Disease - A Mini-Review

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