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Oral treatment with the d-enantiomeric peptide D3 improves the pathology and behavior of Alzheimer's Disease transgenic mice.

ABSTRACT: Several lines of evidence suggest that the amyloid-?-peptide (A?) plays a central role in the pathogenesis of Alzheimer's disease (AD). Not only A? fibrils but also small soluble A? oligomers in particular are suspected to be the major toxic species responsible for disease development and progression. The present study reports on in vitro and in vivo properties of the A? targeting d-enantiomeric amino acid peptide D3. We show that next to plaque load and inflammation reduction, oral application of the peptide improved the cognitive performance of AD transgenic mice. In addition, we provide in vitro data elucidating the potential mechanism underlying the observed in vivo activity of D3. These data suggest that D3 precipitates toxic A? species and converts them into nonamyloidogenic, nonfibrillar, and nontoxic aggregates without increasing the concentration of monomeric A?. Thus, D3 exerts an interesting and novel mechanism of action that abolishes toxic A? oligomers and thereby supports their decisive role in AD development and progression.

SUBMITTER: Aileen Funke S

PROVIDER: S-EPMC3368690 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Oral treatment with the d-enantiomeric peptide D3 improves the pathology and behavior of Alzheimer's Disease transgenic mice.

Aileen Funke Susanne S van Groen Thomas T Kadish Inga I Bartnik Dirk D Nagel-Steger Luitgard L Brener Oleksandr O Sehl Torsten T Batra-Safferling Renu R Moriscot Christine C Schoehn Guy G Horn Anselm H C AH Müller-Schiffmann Andreas A Korth Carsten C Sticht Heinrich H Willbold Dieter D

ACS chemical neuroscience 20100802 9

Several lines of evidence suggest that the amyloid-β-peptide (Aβ) plays a central role in the pathogenesis of Alzheimer's disease (AD). Not only Aβ fibrils but also small soluble Aβ oligomers in particular are suspected to be the major toxic species responsible for disease development and progression. The present study reports on in vitro and in vivo properties of the Aβ targeting d-enantiomeric amino acid peptide D3. We show that next to plaque load and inflammation reduction, oral application ...[more]

PMID: 22778851

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Project description:Alzheimer's disease (AD) is a complex progressive neurodegenerative disorder affecting humans mainly through the deposition of Aβ-amyloid (Aβ) fibrils and accumulation of neurofibrillary tangles in the brain. Currently available AD treatments only exhibit symptomatic relief but do not generally intervene with the amyloid and tau pathologies. The extra-virgin olive oil (EVOO) monophenolic secoiridoid S-(-)-oleocanthal (OC) showed anti-inflammatory activity through COX system inhibition with potency comparable to the standard non-steroidal anti-inflammatory drug (NSAID) like ibuprofen. OC also showed positive in vitro, in vivo, and clinical therapeutic effects against cardiovascular diseases, many malignancies, and AD. Due to its pungent, astringent, and irritant taste, OC should be formulated in acceptable dosage form before its oral use as a potential nutraceutical. The objective of this study is to develop new OC oral formulations, assess whether they maintained OC activity on the attenuation of β-amyloid pathology in a 5xFAD mouse model upon 4-month oral dosing use. Exploration of potential OC formulations underlying molecular mechanism is also within this study scope. OC powder formulation (OC-PF) and OC-solid dispersion formulation with erythritol (OC-SD) were prepared and characterized using FT-IR spectroscopy, powder X-ray diffraction, and scanning electron microscopy (ScEM) analyses. Both formulations showed an improved OC dissolution profile. OC-PF and OC-SD improved memory deficits of 5xFAD mice in behavioral studies. OC-PF and OC-SD exhibited significant attenuation of the accumulation of Aβ plaques and tau phosphorylation in the brain of 5xFAD female mice. Both formulations markedly suppressed C3AR1 (complement component 3a receptor 1) activity by targeting the downstream marker STAT3. Collectively, these results demonstrate the potential for the application of OC-PF as a prospective nutraceutical or dietary supplement to control the progression of amyloid pathogenesis associated with AD.

Project description:Almost all dental diseases are caused by biofilms that consist of multispecies communities. DJK-5, which is a short D-enantiomeric, protease-resistant peptide with broad-spectrum anti-biofilm activity, was tested for its effect on oral multispecies biofilms. Peptide DJK-5 at 10 ?g/mL effectively prevented the growth of these microbes in culture media in a time-dependent manner. In addition to the prevention of growth, peptide DJK-5 completely killed both Streptococcus mutans and Enterococcus faecalis suspended from biofilms after 30 minutes of incubation in liquid culture media. DJK-5 also led to the effective killing of microbes in plaque biofilm. The proportion of bacterial cells killed by 10 ?g/mL of DJK-5 was similar after 1 and 3 days, both exceeding 85%. DJK-5 was able to significantly prevent biofilm formation over 3 days (P = 0.000). After 72 hours of exposure, DJK-5 significantly reduced and almost completely prevented plaque biofilm production by more than 90% of biovolume compared to untreated controls (P = 0.000). The proportion of dead biofilm bacteria at the 10 ?g/mL DJK-5 concentration was similar for 1- and 3-day-old biofilms, whereby >86% of the bacteria were killed. DJK-5 was also able to kill >79% and >85% of bacteria, respectively, after one-time and three brief treatments of 3-day-old biofilms. The combination of DJK-5 and chlorhexidine showed the best bacterial killing among all treatments, with ~83% and >88% of bacterial cells killed after 1 and 3 minutes, respectively. No significant difference was found in the percentage of biofilm killing amongst three donor plaque samples after DJK-5 treatment. In particular, DJK-5 showed strong performance in inhibiting biofilm development and eradicating pre-formed oral biofilms compared to L-enantiomeric peptide 1018. DJK-5 was very effective against oral biofilms when used alone or combined with chlorhexidine, and may be a promising agent for use in oral anti-biofilm strategies in the future.

Project description:BACKGROUND:Amyloid ? (A?)-directed immunotherapy has shown promising results in preclinical and early clinical Alzheimer's disease (AD) trials, but successful translation to late clinics has failed so far. Compelling evidence suggests that post-translationally modified A? peptides might play a decisive role in onset and progression of AD and first clinical trials targeting such A? variants have been initiated. Modified A? represents a small fraction of deposited material in plaques compared to pan-A? epitopes, opening up pathways for tailored approaches of immunotherapy. Here, we generated the first monoclonal antibodies that recognize L-isoaspartate-modified A? (isoD7-A?) and tested a lead antibody molecule in 5xFAD mice. METHODS:This work comprises a combination of chemical and biochemical techniques as well as behavioral analyses. A? peptides, containing L-isoaspartate at position 7, were chemically synthesized and used for immunization of mice and antibody screening methods. Biochemical methods included anti-isoD7-A? monoclonal antibody characterization by surface plasmon resonance, immunohistochemical staining of human and transgenic mouse brain, and the development and application of isoD7-A? ELISA as well as different non-modified A? ELISA. For antibody treatment studies, 12?mg/kg anti-isoD7-A? antibody K11_IgG2a was applied intraperitoneally to 5xFAD mice for 38?weeks. Treatment controls implemented were IgG2a isotype as negative and 3D6_IgG2a, the parent molecule of bapineuzumab, as positive control antibodies. Behavioral studies included elevated plus maze, pole test, and Morris water maze. RESULTS:Our advanced antibody K11 showed a KD in the low nM range and?>?400fold selectivity for isoD7-A? compared to other A? variants. By using this antibody, we demonstrated that formation of isoD7-A? may occur after formation of aggregates; hence, the presence of the isoD7-modification differentiates aged A? from newly formed peptides. Importantly, we also show that the Tottori mutation responsible for early-onset AD in a Japanese pedigree is characterized by massively accelerated formation of isoD7-A? in cell culture. The presence of isoD7-A? was verified by K11 in post mortem human cortex and 5xFAD mouse brain tissue. Passive immunization of 5xFAD mice resulted in a significant reduction of isoD7-A? and total A? in brain. Amelioration of cognitive impairment was demonstrated by Morris water maze, elevated plus maze, pole, and contextual fear conditioning tests. Interestingly, despite the lower abundance of the isoD7-A? epitope, the application of anti-isoD7-A? antibodies showed comparable treatment efficacy in terms of reduction of brain amyloid and spatial learning but did not result in an increase of plasma A? concentration as observed with 3D6 treatment. CONCLUSIONS:The present study demonstrates, for the first time, that the antibody-mediated targeting of isoD7-modified A? peptides leads to attenuation of AD-like amyloid pathology. In conjunction with previously published data on antibodies directed against pGlu-modified A?, the results highlight the crucial role of modified A? peptides in AD pathophysiology. Hence, the results also underscore the therapeutic potential of targeting modified amyloid species for defining tailored approaches in AD therapy.

Dataset Information

Oral treatment with the d-enantiomeric peptide D3 improves the pathology and behavior of Alzheimer's Disease transgenic mice.

Publications

Oral treatment with the d-enantiomeric peptide D3 improves the pathology and behavior of Alzheimer's Disease transgenic mice.

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