A pentavalent peptide vaccine elicits Aβ and tau antibodies with prophylactic activity in an Alzheimer's disease mouse model.

Amyloid-β (Aβ) and hyperphosphorylated tau protein are targets for Alzheimer's Disease (AD) immunotherapies, which are generally focused on single epitopes within Aβ or tau. However, due to the complexity of both Aβ and tau in AD pathogenesis, a multipronged approach simultaneously targeting multiple epitopes of both proteins could overcome limitations of monotherapies. Herein, we propose an active AD immunotherapy based on a nanoparticle vaccine comprising two Aβ peptides (1-14 and pyroglutamate pE3-14) and three tau peptides (centered on phosphorylated pT181, pT217 and pS396/404).

Structural Optimization and Performance of a Low-Frequency Double-Shell Type-IV Flexural Hydroacoustic Transducer.

To amplify the displacement of the radiation shell, a double-shell type-IV curved hydroacoustic transducer was proposed. Through Ansys finite element simulation, the vibration modes of the transducer in different stages and the harmonic response characteristics in air and water were studied, and the bandwidth emission of the hydroacoustic transducer was achieved. By optimizing the size of each component, the resonant frequency of the transducer is 740 Hz, the maximum conductivity was 0.

Diabetic Ketoacidosis Induces Tau Hyperphosphorylation in Rat Brain.

Background: Diabetes mellitus (DM) increases the risk for cognitive impairment and Alzheimer's disease (AD). Diabetic ketoacidosis (DKA), a serious complication of DM, may also cause brain damage and further AD, but the underlying molecular mechanisms remain unclear.

Objective: Our objective was to understand how DKA can promote neurodegeneration in AD.

Two simple assays for assessing the seeding activity of proteopathic tau.

The regional distribution of neurofibrillary tangles of hyperphosphorylated tau aggregates is associated with the progression of Alzheimer's disease (AD). Misfolded proteopathic tau recruits naïve tau and templates its misfolding and aggregation in a prion-like fashion, which is believed to be the molecular basis of propagation of tau pathology. A practical way to assess tau seeding activity is to measure its ability to recruit/bind other tau molecules and to induce tau aggregation.

Genetic polymorphisms of purinergic P2Y receptor were associated with the susceptibility to essential hypertension in Chinese postmenopausal women.

Hypertension has become a prominent public health concern. Essential hypertension (EH) is a polygenic disorder caused by multiple susceptibility genes. It has been previously shown that the purinergic P2Y receptor (P2YR) regulates blood pressure; however, whether P2YR genetic polymorphisms correlate with EH has not been investigated in Chinese.

Gut Microbiota and Immunotherapy for Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that eventually leads to dementia and death of the patient. Currently, no effective treatment is available that can slow or halt the progression of the disease. The gut microbiota can modulate the host immune system in the peripheral and central nervous system through the microbiota-gut-brain axis.

Tau seeding activity in various regions of down syndrome brain assessed by two novel assays.

Propagation of tau pathology via the seeding of naive tau aggregation underlies the progression of Alzheimer's disease (AD) and related tauopathies. Individuals with Down syndrome (DS) develop tau pathology at the fourth decade of life, but tau seeding activity in DS brain has not yet been determined. To measure tau seeding activity, we developed capture assay and seeded-tau aggregation assay with truncated tau.

AKT/GSK-3β signaling is altered through downregulation of mTOR during cerebral Ischemia/Reperfusion injury.

Purpose: Cellular responses following cerebral ischemia/reperfusion injury are critical to recovery and survival after ischemic stroke. Understanding of these cellular responses can help the design of therapies to protect brain tissue and promote recovery after stroke. One of these cellular responses may be mediated by the AKT (protein kinase B) signal transduction pathway.

Multi-Targets: An Unconventional Drug Development Strategy for Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that eventually leads to dementia and death of the patient. Despite the enormous amounts of resources and efforts for AD drug development during the last three decades, no effective treatments have been developed that can slow or halt the progression of the disease. Currently available drugs for treating AD can only improve clinical symptoms temporarily with moderate efficacies.

Thiamme2-G, a Novel O-GlcNAcase Inhibitor, Reduces Tau Hyperphosphorylation and Rescues Cognitive Impairment in Mice.

Background: Abnormal hyperphosphorylation of microtubule-associated protein tau plays a pivotal role in Alzheimer's disease (AD). We previously found that O-GlcNAcylation inversely correlates to hyperphosphorylation of tau in AD brain, and downregulation of brain O-GlcNAcylation promotes tau hyperphosphorylation and AD-like neurodegeneration in mice.

Objective: Herein we investigated the effect of increasing O-GlcNAcylation by using intermittent dosing with low doses of a potent novel O-GlcNAcase (OGA) inhibitor on AD-like brain changes and cognitive function in a mouse model of sporadic AD (sAD) induced by intracerebroventricular (ICV) injection of streptozotocin (STZ).

Alzheimer's disease brain contains tau fractions with differential prion-like activities.

Neurofibrillary tangles (NFTs) made of abnormally hyperphosphorylated tau are a hallmark of Alzheimer's disease (AD) and related tauopathies. Regional distribution of NFTs is associated with the progression of the disease and has been proposed to be a result of prion-like propagation of misfolded tau. Tau in AD brain is heterogenous and presents in various forms.

Sevoflurane-induced neuronal apoptosis in neonatal mice is prevented with intranasal administration of insulin.

Concerns about the potential neurotoxicity of general anesthesia to the developing brain have been increasing in recent years. Animal studies have shown that neonatal exposure to general anesthesia causes both acute neurotoxicity and behavioral abnormalities later in life. In the present study, we observed over-activation of neuronal apoptosis in the brain of neonatal mice after a single exposure to anesthesia with sevoflurane for 6 hours at the age of 7 days.

Truncation of Tau selectively facilitates its pathological activities.

Neurofibrillary tangles of abnormally hyperphosphorylated Tau are a hallmark of Alzheimer's disease (AD) and related tauopathies. Tau is truncated at multiple sites by various proteases in AD brain. Although many studies have reported the effect of truncation on the aggregation of Tau, these studies mostly employed highly artificial conditions, using heparin sulfate or arachidonic acid to induce aggregation.

Intermittent fasting promotes adult hippocampal neuronal differentiation by activating GSK-3β in 3xTg-AD mice.

Moderate dietary restriction can ameliorate age-related chronic diseases such as Alzheimer's disease (AD) by increasing the expression of neurotrophic factors and promoting neurogenesis in the brain. Glycogen synthase kinase-3β (GSK-3β) signaling is essential for the coordination of progenitor cell proliferation and differentiation during brain development. The mechanisms by which GSK-3β is involved in dietary restriction-induced neurogenesis and cognitive improvement remain unclear.

Young blood plasma reduces Alzheimer's disease-like brain pathologies and ameliorates cognitive impairment in 3×Tg-AD mice.

Background: Recent studies indicated that circulatory factors in blood plasma from young animals can reactivate neurogenesis, restore synaptic plasticity, and improve cognitive function in aged animals. Here, we investigated if young plasma could have a possible therapeutic effect for treatment of Alzheimer's disease (AD)-like pathologies and cognitive impairment in triple-transgenic AD (3×Tg-AD) mice.

Methods: We intravenously injected plasma from 2- to 3-month-old C57BL/6 J wild-type mice into 16-17-month-old 3×Tg-AD mice twice a week for 8 weeks.

Neonatal Exposure to Anesthesia Leads to Cognitive Deficits in Old Age: Prevention with Intranasal Administration of Insulin in Mice.

Recent pre-clinical and clinical studies suggest that general anesthesia in infants and children may increase the risk of learning disabilities. Currently, there is no treatment for preventing anesthesia-induced neurotoxicity and potential long-term functional impairment. Animal studies have shown that neonatal exposure to anesthesia can induce acute neurotoxicity and long-term behavioral changes that can be detected a few months later.

Anesthesia with sevoflurane or isoflurane induces severe hypoglycemia in neonatal mice.

Sevoflurane and isoflurane are among the most commonly used general anesthetics for children including infants, but their impact on metabolism, especially on blood glucose level, in children is not well understood. We investigated the impacts of anesthesia of neonatal (7-8 days old) and adult (2-3 months old) mice with the inhalational anesthetics 2.5% sevoflurane or 1.

Melatonin and its metabolite N(1)-acetyl-N(1)-formyl-5-methoxykynuramine improve learning and memory impairment related to Alzheimer's disease in rats.

The aim of this study was to investigate the effect of melatonin (MT) and its metabolite N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (AFMK) on Alzheimer-like learning and memory impairment in rats intracerebroventricularly injected with streptozotocin (STZ). The results showed that the escape latency of the STZ group was longer than that of the control (CON), MT, and AFMK groups. Increased levels of hyperphosphorylated tau, neurofilament proteins, and malondialdehyde and decreased superoxide dismutase levels were observed in the brains of the rats from the STZ group compared with the brains of the rats from the CON, MT, AFMK high and low group.

Glycogen synthase kinase-3β suppresses the expression of protein phosphatase methylesterase-1 through β-catenin.

Protein phosphatase 2A (PP2A) is the major tau phosphatase. Its activity toward tau is regulated by the methylation of PP2A catalytic subunit (PP2Ac) at Leu309. Protein phosphatase methylesterase-1 (PME-1) demethylates PP2Ac and suppresses its activity.