Development of a system to analyze oral frailty associated with Alzheimer's disease using a mouse model.

The rapid aging of the population makes the detection and prevention of frailty increasingly important. Oral frailty has been proposed as a novel frailty phenotype and is defined as a decrease in oral function coexisting with a decline in cognitive and physical functions. Oral frailty has received particular attention in relation to Alzheimer's disease (AD).

Age-related functional decline of human B cells.

This study aimed to investigate the changes in B cell functional decline and antigen sensitization with aging using two Epstein Barr virus (EBV)-immortalized human B cell lines, one from a 22-year-old man (EBV-B young) and the other from a 65-year-old man (EBV-B old). The activity of senescence-associated β-galactosidase, a marker of cellular senescence, was enhanced in the EBV-B old cells compared with EBV-B young cells. Moreover, the levels of , , , -, and -, which are senescence-associated secretary phenotypes, were also increased in EBV-B old cells.

Learning Deficits Accompanied by Microglial Proliferation After the Long-Term Post-Injection of Alzheimer's Disease Brain Extract in Mouse Brains.

Background: Human tauopathy brain injections into the mouse brain induce the development of tau aggregates, which spread to functionally connected brain regions; however, the features of this neurotoxicity remain unclear. One reason may be short observational periods because previous studies mostly used mutated-tau transgenic mice and needed to complete the study before these mice developed neurofibrillary tangles.

Objective: To examine whether long-term incubation of Alzheimer's disease (AD) brain in the mouse brain cause functional decline.

Asparagine residue 368 is involved in Alzheimer's disease tau strain-specific aggregation.

In tauopathies, tau forms pathogenic fibrils with distinct conformations (termed "tau strains") and acts as an aggregation "seed" templating the conversion of normal tau into isomorphic fibrils. Previous research showed that the aggregation core of tau fibril covers the C-terminal region (243-406 amino acids (aa)) and differs among the diseases. However, the mechanisms by which distinct fibrous structures are formed and inherited via templated aggregation are still unknown.

An Oral Aβ Vaccine Using a Recombinant Adeno-Associated Virus Vector in Aged Monkeys: Reduction in Plaque Amyloid and Increase in Aβ Oligomers.

With the objective to improve the amyloid-β (Aβ) targeting immunotherapy, we investigated the safety and efficacy of an oral vaccine with recombinant adeno-associated virus vector carrying a signal sequence and Aβ1-43 cDNA (rAAV/Aβ) in old non-human primates, 12 African green and 10 cynomolgus monkeys. The enteric-dissolving coated capsules containing rAAV/Aβ were orally administered once or twice, then monkeys' conditions were carefully observed with complete blood count and laboratory examinations of the sera. General conditions, food intake, water intake, stool conditions, body weight changes, and menstruation cycles were not significantly altered, and laboratory tests and pathological examinations of the systemic organs were unremarkable.

Involvement of the Septo-Hippocampal Cholinergic Pathway in Association with Septal Acetylcholinesterase Upregulation in a Mouse Model of Tauopathy.

Background: Cholinergic cell loss in the basal forebrain, the major source of hippocampal cholinergic projections, has been implicated in Alzheimer's disease.

Objective: To examine whether the septohippocampal pathway is involved in tauopathy model mice and to elucidate the tau-associated mechanism underlying cholinergic alteration.

Methods: Adult (6 to 8 months old) and old (16 to 18 months old) transgenic mice expressing wild-type human tau, Tg601, were examined using Ex vivo diffusion tensor magnetic resonance imaging (DTI) and 2-[18F]fluoro- 2-deoxy-D-glucose positron emission tomography (FDG-PET).

Region-Specific Vulnerability to Oxidative Stress, Neuroinflammation, and Tau Hyperphosphorylation in Experimental Diabetes Mellitus Mice.

Recent epidemiological evidence suggests that diabetes mellitus (DM) is a risk factor for Alzheimer's disease (AD). One of the pathological hallmarks of AD is hyperphosphorylated tau protein, which forms neurofibrillary tangles. Oxidative stress and the activation of inflammatory pathways are features that are associated with both DM and AD.

Short-term treadmill exercise increased tau insolubility and neuroinflammation in tauopathy model mice.

Physical exercise has been identified as a preventive measure for Alzheimer's disease (AD), one of the neuropathological hallmarks of which, neurofibrillary tangles, consist of hyperphosphorylated insoluble tau. Previous studies demonstrated that long-term treadmill exercise reduced tau hyperphosphorylation and insolubility; however, whether short-term treadmill exercise (STE) alters tau modifications currently remains unknown. In the present study, we attempted to characterize the effects of STE on tau solubility and determine its relationship with neuroinflammation using tauopathy model mice (Tg601), which express wild-type human tau.

The twenty-four KDa C-terminal tau fragment increases with aging in tauopathy mice: implications of prion-like properties.

The truncated tau protein is a component of the neurofibrillary tangles found in the brains with tauopathies. However, the molecular mechanisms by which the truncated tau fragment causes neurodegeneration remain unknown. Tau pathology was recently suggested to spread through intercellular propagation, and required the formation of 'prion-like' species.

Suppression of immunoglobulin production in human peripheral blood mononuclear cells by monocytes via secretion of heavy-chain ferritin.

In vitro antigen stimulation of peripheral blood mononuclear cells (PBMCs) does not induce immunoglobulin (Ig) production. However, pretreatment of PBMCs with l-leucyl-l-leucine methyl ester (LLME) prior to in vitro stimulation removes the suppression of Ig production. In the present study, we attempted to identify the target cells of LLME and determine the mechanisms by which Ig production in PBMCs is suppressed.

In vitro immunization of Epstein-Barr virus-immortalized B cells augments antigen-specific antibody production.

The current method for in vitro immunization (IVI) uses several antigens including toxins, food allergens, pathogenic bacteria, and self-antigen-derived peptides that induce an antigen-specific immune response in peripheral blood mononuclear cells (PBMCs). This protocol, however, requires donor blood collection and preparation of PBMCs before every IVI. In the present study, we aimed to design a more efficient system utilizing B cells immortalized with Epstein-Barr virus (EBV-B) as host cells for IVI to make antigen-specific antibodies.

Chronic intermittent hypoxia/reoxygenation facilitate amyloid-β generation in mice.

Previous studies have shown a high prevalence of obstructive sleep apnea (OSA) among patients with Alzheimer's disease (AD). However, it is poorly assessed whether chronic intermittent hypoxia (CIH), which is a characteristic of OSA, affects the pathophysiology of AD. We aimed to investigate the direct effect of intermittent hypoxia (IH) in pathophysiology of AD in vivo and in vitro.

[Development of antibodies for immunotherapy of Alzheimer's disease].

Based on the amyloid cascade hypothesis, immunotherapy targeting amyloid β (Aβ) for Alzheimer's disease (AD) has been developed. It was reported that active immunization using Aβ peptide attenuates amyloid deposits and memory impairment in AD model mice. However, active immunization of patients with AD (AN-1792) was halted due to adverse effects in which a subset of patients developed meningoencephalitis.

Urinary homocysteic acid levels correlate with mini-mental state examination scores in Alzheimer's disease patients.

Homocysteic acid (HA) has been suggested as a pathogen in a mouse model of Alzheimer's disease (AD), 3xTg-AD. However, it is not established whether HA is involved in humans. We investigated the relationship between urinary HA levels and Mini-Mental State Examination (MMSE) scores in AD patients (n = 70) and non-AD controls (n = 34).

[Antibody therapy for Alzheimer's disease].

In order to avoid Abeta-induced autoimmune encephalitis, several monoclonal and polyclonal antibodies are in clinical trials. These are bapineuzumab, solanezumab, ponezumab, gantenerumab, BAN2401, gammaguard and octagam. Since each antibody has a different antigen epitope of Abeta, anti-amyloid activities are different.

Long-term oral lithium treatment attenuates motor disturbance in tauopathy model mice: implications of autophagy promotion.

Lithium, a drug used to treat bipolar disorders, has a variety of neuroprotective mechanisms including inhibition of glycogen synthase kinase-3 (GSK-3), a major tau kinase. Recently, it has been shown that, in various neurodegenerative proteinopathies, lithium could induce autophagy. To analyze how lithium is therapeutically beneficial in tauopathies, transgenic mice overexpressing human mutant tau (P301L) were treated with oral lithium chloride (LiCl) for 4 months starting at the age of 5 months.

[Current trend of immunotherapy for Alzheimer's disease].

Immunotherapy targeting amyloidbeta (Abeta) for Alzheimer's disease (AD) has been developed based on the amyloid cascade hypothesis. It was shown that active immunization using Abeta peptide attenuates amyloid deposits and memory impairment in AD model mice. However, active immunization of patients with AD (AN1792) was halted because 6 % of patients developed meningoencephalitis.

Generation of a human anti-tumor necrosis factor-α monoclonal antibody by in vitro immunization with a multiple antigen peptide.

We developed the in vitro immunization method to induce antigen-specific immune responses in human peripheral blood mononuclear cells (PBMCs). However, when we used a peptide as sensitizing antigen, the antigen-specific immune response was found to be weak, and hence, we could not effectively obtain the antigen-specific antibody gene. In the present study, we attempted to improve the in vitro immunization method by augmenting the immune response to the peptide antigen.

Production of human monoclonal antibodies against Fc(epsilon)RI(alpha) by a method combining in vitro immunization with phage display.

An in vitro immunization protocol using human peripheral blood mononuclear cells (PBMC) was developed to generate human antigen-specific antibodies. Monoclonal antibodies have great potential, and in particular, efficient acquirement of monoclonal antibodies against membrane proteins provides advantages. In this study, we tried to generate a human monoclonal antibody against the high affinity IgE receptor, Fc(epsilon)RI(alpha), using a method combining in vitro immunization and phage display.

Generation of human monoclonal antibodies against Propionibacterium acnes by applying the phage display method to human peripheral blood mononuclear cells immunized in vitro.

Propionibacterium acnes is a gram-positive, non-spore-forming, rod-shaped bacterium that is often detected in normal human skin flora. P. acnes has been associated with many diseases.

Different individual immune responses elicited by in vitro immunization.

We have previously demonstrated that the addition of muramyl dipeptide (MDP), interleukin-2 (IL-2) and IL-4 effectively raises antibody production from L-Leucyl-L-leucine methyl ester (LLME)-treated human peripheral blood lymphocytes (PBLs) against specific soluble antigen when immunized in vitro. However, PBLs from individual donors were separate optimal conditions regarding concentrations for IL-2 and IL-4, which in turn required us to optimize each individual PBLs to effectively produce antigen specific human antibody by in vitro immunization. These individual differences in the requirement for IL-2 and IL-4 reflects the differences in individual immune responses against a specific soluble antigen, which can be elicited by in vitro immunization.