Testing a MultiTEP-based combination vaccine to reduce Aβ and tau pathology in Tau22/5xFAD bigenic mice.

BackgroundAlzheimer disease (AD) is characterized by the accumulation of beta-amyloid (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau, which together lead to neurodegeneration and cognitive decline. Current therapeutic approaches have primarily aimed to reduce pathological aggregates of either Aβ or tau, yet phase 3 clinical trials of these approaches have thus far failed to delay disease progression in humans. Strong preclinical evidence indicates that these two abnormally aggregated proteins interact synergistically to drive downstream neurodegeneration. Therefore, combinatorial therapies that concurrently target both Aβ and tau might be needed for effective disease modification.MethodsA combinatorial vaccination approach was designed to concurrently target both Aβ and tau pathologies. Tau22/5xFAD (T5x) bigenic mice that develop both pathological Aβ and tau aggregates were injected intramuscularly with a mixture of two MultiTEP epitope vaccines: AV-1959R and AV-1980R, targeting Aβ and tau, respectively, and formulated in AdvaxCpG, a potent polysaccharide adjuvant. Antibody responses of vaccinated animals were measured by ELISA, and neuropathological changes were determined in brain homogenates of vaccinated and control mice using ELISA and Meso Scale Discovery (MSD) multiplex assays.ResultsT5x mice immunized with a mixture of Aβ- and tau-targeting vaccines generated high Aβ- and tau-specific antibody titers that recognized senile plaques and neurofibrillary tangles/neuropil threads in human AD brain sections. Production of these antibodies in turn led to significant reductions in the levels of soluble and insoluble total tau, and hyperphosphorylated tau as well as insoluble Aβ42, within the brains of bigenic T5x mice.ConclusionsAV-1959R and AV-1980R formulated with AdvaxCpG adjuvant are immunogenic and therapeutically potent vaccines that in combination can effectively reduce both of the hallmark pathologies of AD in bigenic mice. Taken together, these findings warrant further development of this vaccine technology for ultimate testing in human AD

The immunological potency and therapeutic potential of a prototype dual vaccine against influenza and Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>Numerous pre-clinical studies and clinical trials demonstrated that induction of antibodies to the β-amyloid peptide of 42 residues (Aβ₄₂) elicits therapeutic effects in Alzheimer's disease (AD). However, an active vaccination strategy based on full length Aβ₄₂is currently hampered by elicitation of T cell pathological autoreactivity. We attempt to improve vaccine efficacy by creating a novel chimeric flu vaccine expressing the small immunodominant B cell epitope of Aβ₄₂. We hypothesized that in elderly people with pre-existing memory Th cells specific to influenza this dual vaccine will simultaneously boost anti-influenza immunity and induce production of therapeutically active anti-Aβ antibodies.</p> <p>Methods</p> <p>Plasmid-based reverse genetics system was used for the rescue of recombinant influenza virus containing immunodominant B cell epitopes of Aβ₄₂(Aβ_1-7/10).</p> <p>Results</p> <p>Two chimeric flu viruses expressing either 7 or 10 aa of Aβ₄₂(flu-Aβ_1-7or flu-Aβ_1-10) were generated and tested in mice as conventional inactivated vaccines. We demonstrated that this dual vaccine induced therapeutically potent anti-Aβ antibodies and anti-influenza antibodies in mice.</p> <p>Conclusion</p> <p>We suggest that this strategy might be beneficial for treatment of AD patients as well as for prevention of development of AD pathology in pre-symptomatic individuals while concurrently boosting immunity against influenza.</p

Reducing AD-Like Pathology in 3xTg-AD Mouse Model by DNA Epitope Vaccine — A Novel Immunotherapeutic Strategy

BACKGROUND: The development of a safe and effective AD vaccine requires a delicate balance between providing an adequate anti-Abeta antibody response sufficient to provide therapeutic benefit, while eliminating an adverse T cell-mediated proinflammatory autoimmune response. To achieve this goal we have designed a prototype chemokine-based DNA epitope vaccine expressing a fusion protein that consists of 3 copies of the self-B cell epitope of Abeta(42) (Abeta(1-11)) , a non-self T helper cell epitope (PADRE), and macrophage-derived chemokine (MDC/CCL22) as a molecular adjuvant to promote a strong anti-inflammatory Th2 phenotype. METHODS AND FINDINGS: We generated pMDC-3Abeta(1-11)-PADRE construct and immunized 3xTg-AD mouse model starting at age of 3-4 months old. We demonstrated that prophylactic immunizations with the DNA epitope vaccine generated a robust Th2 immune response that induced high titers of anti-Abeta antibody, which in turn inhibited accumulation of Abeta pathology in the brains of older mice. Importantly, vaccination reduced glial activation and prevented the development of behavioral deficits in aged animals without increasing the incidence of microhemorrhages. CONCLUSIONS: Data from this transitional pre-clinical study suggest that our DNA epitope vaccine could be used as a safe and effective strategy for AD therapy. Future safety and immunology studies in large animals with the goal to achieve effective humoral immunity without adverse effects should help to translate this study to human clinical trials

Autoimmunity to HSP60 during diet induced obesity in mice

Adaptive immunity has been implicated in adipose tissue inflammation, obesity and its adverse metabolic consequences. No obesity-related autoantigen has yet been identified, although heat shock protein 60 (HSP60) has been implicated in other autoimmune diseases. We investigated whether feeding a high-fat diet to C57BL/6J mice would cause autoimmunity to HSP60 and whether immunomodulation with peptides from HSP60 would reverse the resulting obesity or metabolic dysfunction. Obese mice had higher circulating levels of HSP60 associated with increased T-lymphocyte proliferation responses and the emergence of circulating IgG1 and IgG2c antibody levels against HSP60. Treatment with escalating doses of a mixture of three proven immunomodulatory HSP60 peptides did not reduce weight but completely reversed the increase in VLDL/LDL levels and partially reversed the glucose intolerance in obese mice. Obese mice mount an autoimmune response to HSP60, which partly underlies the resulting metabolic disturbances

Спектрофотометрическое определение аскорбиновой кислоты с использованием гетерополикомплекса структуры Доусона

Исследовано восстановление 18-молибдодифосфорного гетерополикомплекса аскорбиновой кислотой. Разработана экспрессная методика спектрофотометрического определения аскорбиновой кислоты в фармацевтических препаратах и пищевых продуктах

Спектрофотометричне визначення аскорбінової кислоти з використанням гетерополікомплексу структури Доусона

Исследовано восстановление 18-молибдодифосфорного гетерополикомплекса аскорбиновой кислотой. Разработана экспрессная методика спектрофотометрического определения аскорбиновой кислоты в фармацевтических препаратах и пищевых продуктах.Досліджено  відновлення18-молібдодифосфорного  гетерополікомплекса  аскорбіновоюкислотою.  Розроблена  експресна  методика  спектрофотометричного  визначення  аскорбінової кислоти у фармацевтичних препаратах та харчових продукта

ORGANIZATIONAL ASPECTS OF OUTPATIENT SURGICAL CARE FOR PATIENTS WITH CATARACT IN THE KALUGA BRANCH OF THE S. FYODOROV EYE MICROSURGERY FEDERAL STATE INSTITUTUION

Purpose. Is to consider the organizational aspects of outpatient cataract surgery in the Kaluga branch of the S. Fyodorov Eye Microsurgery Federal State Institutuion and evaluate its effectiveness.Material and methods. The outpatient cataract surgery established in Kaluga branch is a type of hospital-replacing forms and involves hospitalization, surgery, nearest postoperative period and the patient’s discharged in the same day, that is not required inpatient medical care. The modern technologies in cataract surgery actively use in clinical practice of the Kaluga branch of Eye Microsurgery, that allow to perform operations on an outpatient basis.Results. During 2015-2016 in the Kaluga branch of Eye Microsurgery in 12 357 cataract surgeries were performed, including 11 368 (92%) in outpatient regime. The number of surgeries increases by 36% as compared with the same period before the outpatient surgical care began to use. The clinical and functional results of the outpatient cataract surgery are high, despite the absence of postoperative follow-up in inpatient regime. Besides, the majority of patients are satisfied with the absence of hospitalization and possibility to be at home after undergoing surgery. Alongside with the clinical effectiveness the outpatient treatment is resulted in considerable economic effect.Conclusions. Outpatient medical surgical care allows to perform major volume of operative treatment, ensuring the effectiveness and safety of cataract surgery and is a promising direction of the healthcare development