Regulation of Diabetes: a Therapeutic Strategy for Alzheimer's Disease?

Accumulated evidence suggests that sporadic cases of Alzheimer's disease (AD) make up more than 95% of total AD patients, and diabetes has been implicated as a strong risk factor for the development of AD. Diabetes shares pathological features of AD, such as impaired insulin signaling, increased oxidative stress, increased amyloid-beta (Aß) production, tauopathy and cerebrovascular complication. Due to shared pathologies between the two diseases, anti-diabetic drugs may be a suitable therapeutic option for AD treatment. In this article, we will discuss the well-known pathologies of AD, including Aß plaques and tau tangles, as well as other mechanisms shared in AD and diabetes including reactive glia and the breakdown of blood brain barrier in order to evaluate the presence of any potential, indirect or direct links of pre-diabetic conditions to AD pathology. In addition, clinical evidence of high incidence of diabetic patients to the development of AD are described together with application of anti-diabetic medications to AD patients.

Challenges in the Discovery and Optimization of mGlu2/4 Heterodimer Positive Allosteric Modulators.

BACKGROUND: This article describes the challenges in the discovery and optimization of mGlu2/4 heterodimer Positive Allosteric Modulators (PAMs). METHODS: Initial forays based on VU0155041, a PAM of both the mGlu4 homodimer and the mGlu2/4 heterodimer, led to flat, intractable SAR that precluded advancement. Screening of a collection of 1,152 FDA approved drugs led to the discovery that febuxostat, an approved xanthine oxidase inhibitor, was a moderately potent PAM of the mGlu2/4 heterodimer (EC50 = 3.4 µM), but was peripherally restricted (rat Kp = 0.03). Optimization of this hit led to PAMs with improved potency (EC50s <800 nM) and improved CNS penetration (rat Kp >2, an ~100-fold increase). RESULTS: However, these new amide analogs of febuxostat proved to be either GIRK1/2 and GIRK1/4 activators (primary carboxamide congeners) or mGlu2 PAMs (secondary and tertiary amides) and not selective mGlu2/4 heterodimer PAMs. CONCLUSION: These results required the team to develop a new screening cascade paradigm, and exemplified the challenges in developing allosteric ligands for heterodimeric receptors.

"Sounding Black": Speech Stereotypicality Activates Racial Stereotypes and Expectations About Appearance.

Black Americans who are perceived as more racially phenotypical-that is, who possess more physical traits that are closely associated with their race-are more often associated with racial stereotypes. These stereotypes, including assumptions about criminality, can influence how Black Americans are treated by the legal system. However, it is unclear whether other forms of racial stereotypicality, such as a person's way of speaking, also activate stereotypes about Black Americans. We investigated the links between speech stereotypicality and racial stereotypes (Experiment 1) and racial phenotype bias (Experiment 2). In Experiment 1, participants listened to audio recordings of Black speakers and rated how stereotypical they found the speaker, the likely race and nationality of the speaker, and indicated which adjectives the average person would likely associate with this speaker. In Experiment 2, participants listened to recordings of weakly or strongly stereotypical Black American speakers and indicated which of two faces (either weakly or strongly phenotypical) was more likely to be the speaker's. We found that speakers whose voices were rated as more highly stereotypical for Black Americans were more likely to be associated with stereotypes about Black Americans (Experiment 1) and with more stereotypically Black faces (Experiment 2). These findings indicate that speech stereotypicality activates racial stereotypes as well as expectations about the stereotypicality of an individual's appearance. As a result, the activation of stereotypes based on speech may lead to bias in suspect descriptions or eyewitness identifications.

A novel selective muscarinic acetylcholine receptor subtype 1 antagonist reduces seizures without impairing hippocampus-dependent learning.

Previous studies suggest that selective antagonists of specific subtypes of muscarinic acetylcholine receptors (mAChRs) may provide a novel approach for the treatment of certain central nervous system (CNS) disorders, including epileptic disorders, Parkinson's disease, and dystonia. Unfortunately, previously reported antagonists are not highly selective for specific mAChR subtypes, making it difficult to definitively establish the functional roles and therapeutic potential for individual subtypes of this receptor subfamily. The M(1) mAChR is of particular interest as a potential target for treatment of CNS disorders. We now report the discovery of a novel selective antagonist of M(1) mAChRs, termed VU0255035 [N-(3-oxo-3-(4-(pyridine-4-yl)piperazin-1-yl)propyl)-benzo[c][1,2,5]thiadiazole-4 sulfonamide]. Equilibrium radioligand binding and functional studies demonstrate a greater than 75-fold selectivity of VU0255035 for M(1) mAChRs relative to M(2)-M(5). Molecular pharmacology and mutagenesis studies indicate that VU0255035 is a competitive orthosteric antagonist of M(1) mAChRs, a surprising finding given the high level of M(1) mAChR selectivity relative to other orthosteric antagonists. Whole-cell patch-clamp recordings demonstrate that VU0255035 inhibits potentiation of N-methyl-D-aspartate receptor currents by the muscarinic agonist carbachol in hippocampal pyramidal cells. VU0255035 has excellent brain penetration in vivo and is efficacious in reducing pilocarpine-induced seizures in mice. We were surprised to find that doses of VU0255035 that reduce pilocarpine-induced seizures do not induce deficits in contextual freezing, a measure of hippocampus-dependent learning that is disrupted by nonselective mAChR antagonists. Taken together, these data suggest that selective antagonists of M(1) mAChRs do not induce the severe cognitive deficits seen with nonselective mAChR antagonists and could provide a novel approach for the treatment certain of CNS disorders.

Synthesis and SAR of a novel positive allosteric modulator (PAM) of the metabotropic glutamate receptor 4 (mGluR4).

This Letter describes the synthesis and SAR of the novel positive allosteric modulator, VU0155041, a compound that has shown in vivo efficacy in rodent models of Parkinson's disease. The synthesis takes advantage of an iterative parallel synthesis approach to rapidly synthesize and evaluate a number of analogs of VU0155041.

Labeling and Imaging of Amyloid Plaques in Brain Tissue Using the Natural Polyphenol Curcumin.

Deposition of amyloid beta protein (Aß) in extra- and intracellular spaces is one of the hallmark pathologies of Alzheimer's disease (AD). Therefore, detection of the presence of Aß in AD brain tissue is a valuable tool for developing new treatments to prevent the progression of AD. Several classical amyloid binding dyes, fluorochrome, imaging probes, and Aß-specific antibodies have been used to detect Aß histochemically in AD brain tissue. Use of these compounds for Aß detection is costly and time consuming. However, because of its intense fluorescent activity, high-affinity, and specificity for Aß, as well as structural similarities with traditional amyloid binding dyes, curcumin (Cur) is a promising candidate for labeling and imaging of Aß plaques in postmortem brain tissue. It is a natural polyphenol from the herb Curcuma longa. In the present study, Cur was used to histochemically label Aß plaques from both a genetic mouse model of 5x familial Alzheimer's disease (5xFAD) and from human AD tissue within a minute. The labeling capability of Cur was compared to conventional amyloid binding dyes, such as thioflavin-S (Thio-S), Congo red (CR), and Fluoro-jade C (FJC), as well as Aß-specific antibodies (6E10 and A11). We observed that Cur is the most inexpensive and quickest way to label and image Aß plaques when compared to these conventional dyes and is comparable to Aß-specific antibodies. In addition, Cur binds with most Aß species, such as oligomers and fibrils. Therefore, Cur could be used as the most cost-effective, simple, and quick fluorochrome detection agent for Aß plaques.

VU0810464, a non-urea G protein-gated inwardly rectifying K+ (Kir 3/GIRK) channel activator, exhibits enhanced selectivity for neuronal Kir 3 channels and reduces stress-induced hyperthermia in mice.

BACKGROUND AND PURPOSE: G protein-gated inwardly rectifying K+ (Kir 3) channels moderate the activity of excitable cells and have been implicated in neurological disorders and cardiac arrhythmias. Most neuronal Kir 3 channels consist of Kir 3.1 and Kir 3.2 subtypes, while cardiac Kir 3 channels consist of Kir 3.1 and Kir 3.4 subtypes. Previously, we identified a family of urea-containing Kir 3 channel activators, but these molecules exhibit suboptimal pharmacokinetic properties and modest selectivity for Kir 3.1/3.2 relative to Kir 3.1/3.4 channels. Here, we characterize a non-urea activator, VU0810464, which displays nanomolar potency as a Kir 3.1/3.2 activator, improved selectivity for neuronal Kir 3 channels, and improved brain penetration. EXPERIMENTAL APPROACH: We used whole-cell electrophysiology to measure the efficacy and potency of VU0810464 in neurons and the selectivity of VU0810464 for neuronal and cardiac Kir 3 channel subtypes. We tested VU0810464 in vivo in stress-induced hyperthermia and elevated plus maze paradigms. Parallel studies with ML297, the prototypical activator of Kir 3.1-containing Kir 3 channels, were performed to permit direct comparisons. KEY RESULTS: VU0810464 and ML297 exhibited comparable efficacy and potency as neuronal Kir 3 channel activators, but VU0810464 was more selective for neuronal Kir 3 channels. VU0810464, like ML297, reduced stress-induced hyperthermia in a Kir 3-dependent manner in mice. ML297, but not VU0810464, decreased anxiety-related behaviour as assessed with the elevated plus maze test. CONCLUSION AND IMPLICATIONS: VU0810464 represents a new class of Kir 3 channel activator with enhanced selectivity for Kir 3.1/3.2 channels. VU0810464 may be useful for examining Kir 3.1/3.2 channel contributions to complex behaviours and for probing the potential of Kir 3 channel-dependent manipulations to treat neurological disorders.

Adjuvant docetaxel for node-positive breast cancer.

BACKGROUND: We compared docetaxel plus doxorubicin and cyclophosphamide (TAC) with fluorouracil plus doxorubicin and cyclophosphamide (FAC) as adjuvant chemotherapy for operable node-positive breast cancer. METHODS: We randomly assigned 1491 women with axillary node-positive breast cancer to six cycles of treatment with either TAC or FAC as adjuvant chemotherapy after surgery. The primary end point was disease-free survival. RESULTS: At a median follow-up of 55 months, the estimated rates of disease-free survival at five years were 75 percent among the 745 patients randomly assigned to receive TAC and 68 percent among the 746 randomly assigned to receive FAC, representing a 28 percent reduction in the risk of relapse (P=0.001) in the TAC group. The estimated rates of overall survival at five years were 87 percent and 81 percent, respectively. Treatment with TAC resulted in a 30 percent reduction in the risk of death (P=0.008). The incidence of grade 3 or 4 neutropenia was 65.5 percent in the TAC group and 49.3 percent in the FAC group (P<0.001); rates of febrile neutropenia were 24.7 percent and 2.5 percent, respectively (P<0.001). Grade 3 or 4 infections occurred in 3.9 percent of the patients who received TAC and 2.2 percent of those who received FAC (P=0.05); no deaths occurred as a result of infection. Two patients in each group died during treatment. Congestive heart failure and acute myeloid leukemia occurred in less than 2 percent of the patients in each group. Quality-of-life scores decreased during chemotherapy but returned to baseline levels after treatment. CONCLUSIONS: Adjuvant chemotherapy with TAC, as compared with FAC, significantly improves the rates of disease-free and overall survival among women with operable node-positive breast cancer.

Synthesis and SAR of selective muscarinic acetylcholine receptor subtype 1 (M1 mAChR) antagonists.

This Letter describes the synthesis and SAR, developed through an iterative analogue library approach, of a novel series of selective M1 mAChR antagonists for the potential treatment of Parkinson's disease, dystonia and other movement disorders. Compounds in this series possess M1 antagonist IC(50)s in the 441nM-19microM range with 8- to >340-fold functional selectivity versus rM2-rM5.

Radiation resistant PIDECα cell using photon intermediate direct energy conversion and a 210Po source.

Radiation damage is a significant concern with both alphavoltaic and betavoltaic cells because their performance degrades, especially with high-energy - (>200keV) beta and alpha particles. Indirect excitation methods, such as the Photon Intermediate Direct Energy Conversion (PIDEC) framework, can protect the transducer from radiation. A nuclear battery using a 90Sr beta source was constructed by the author's research group, which demonstrated the radiation resistance of a PIDEC cell driven by beta particles (PIDECß cell). Use of alpha sources to drive nuclear batteries would appear to be much more attractive than beta sources due to higher potential power density. However, they are also subject to higher rates of radiation damage. This paper describes the successful incorporation of alpha particles into the PIDEC framework using the alpha emitter 210Po to form a PIDECα cell. The PIDECα cell transducer was exposed to alpha particles for over one year without experiencing adverse effects from radiation damage.

Mechanisms of early insulin-sensitizing effects of thiazolidinediones in type 2 diabetes.

Whereas thiazolidinediones (TZDs) are known to rapidly improve insulin action in animals, short durations of TZD therapy have never been studied in humans. Among the many known actions of TZDs, increased circulating levels of the high molecular weight (HMW) multimer of adiponectin may be an important insulin-sensitizing mechanism. We examined the effects of only 21 days of 45 mg of pioglitazone (P+) versus placebo (P-) in nine subjects with type 2 diabetes (HbA(1c), 10.9 +/- 0.6%; BMI, 31.9 +/- 1.5 kg/m(2)). Total adiponectin levels increased by approximately twofold in P+ in association with increased adipose tissue gene expression. However, plasma free fatty acid and glucose levels were unchanged, and there were only minimal changes in other "adipokines." Glucose fluxes ([3-(3)H]glucose infusion) were measured during 6-h euglycemic (5 mmol/l) "pancreatic clamp" studies (somatostatin/glucagon/growth hormone) with stepped insulin levels. Pioglitazone induced marked decreases in endogenous glucose production (P+ = 0.9 +/- 0.1 vs. P- = 1.7 +/- 0.3 mg. kg(-1). min(-1); P < 0.05) at physiologic hyperinsulinemia ( approximately 50 microU/ml), which was highly correlated with an increased ratio of HMW adiponectin/total levels (r(2) = 0.90). Maximal insulin stimulation ( approximately 400 microU/ml) revealed pioglitazone-associated increases in glucose uptake (P+ = 10.5 +/- 0.9 vs. P- = 8.9 +/- 0.8 mg. kg(-1). min(-1); P < 0.05), which did not correlate with HMW or total adiponectin levels. Thus, only 21 days of pioglitazone therapy improved insulin action in humans with type 2 diabetes. Increased abundance of the HMW adiponectin multimer may contribute to the hepatic insulin-sensitizing effects of these agents.

Hypnotizability, not suggestion, influences false memory development.

Hypnotizability influences the development of false memories. In Experiment 1, participants heard a positive or negative suggestion regarding hypnosis and then listened to 8 Deese-Roediger-McDermott (DRM) false memory paradigm lists in a hypnotic state. Neither hypnosis nor prehypnotic suggestion affected memory. Highly hypnotizable participants were more accurate in recall and recognition. In Experiment 2, suggestions were delivered in the form of feedback. Participants heard a positive or negative suggestion about their performance prior to either the encoding or retrieval of 8 DRM lists. Neither accurate nor false memories were affected by the suggestion. Highly hypnotizable individuals recognized fewer critical lures if they received a negative suggestion about their performance. These results highlight the unusual role of hypnotizability in the creation of false memories.

Correlates of the multidimensional construct of hypnotizability: paranormal belief, fantasy proneness, magical ideation, and dissociation.

Hypnotizability is a multifaceted construct that may relate to multiple aspects of personality and beliefs. This study sought to address 4 known correlates of hypnotizability to aid in its understanding. Eighty undergraduates completed the Magical Ideation Scale (MIS), the Creative Experiences Questionnaire (CEQ), the Australian Sheep-Goat Scale (ASGS), and the Dissociative Experiences Scale (DES) and then were administered the Creative Imagination Scale (CIS). All 5 scales were significantly correlated. Participants higher in hypnotizability scored higher on the CEQ and the MIS. The findings demonstrate the influence of fantasy proneness and magical thinking on hypnotizability and support the theory that hypnotizability is a complex interaction of multiple traits.

Expression of Alzheimer-Type Neurofibrillary Epitopes in Primary Rat Cortical Neurons Following Infection with Enterococcus faecalis.

The neurofibrillary tau pathology and amyloid deposits seen in Alzheimer's disease (AD) also have been seen in bacteria-infected brains. However, few studies have examined the role of these bacteria in the generation of tau pathology. One suggested link between infection and AD is edentulism, the complete loss of teeth. Edentulism can result from chronic periodontal disease due to infection by Enterococcus faecalis. The current study assessed the ability to generate early Alzheimer-like neurofibrillary epitopes in primary rat cortical neurons through bacterial infection by E. faecalis. Seven-day old cultured neurons were infected with E. faecalis for 24 and 48 h. An upward molecular weight shift in tau by Western blotting (WB) and increased appearance of tau reactivity in cell bodies and degenerating neurites was found in the 48 h infection group for the antibody CP13 (phospho-Serine 202). A substantial increase in reactivity of Alz-50 was seen at 24 and 48 h after infection. Furthermore, extensive microtubule-associated protein 2 (MAP2) reactivity also was seen at 24 and 48 h post-infection. Our preliminary findings suggest a potential link between E. faecalis infection and intracellular changes that may help facilitate early AD-like neurofibrillary pathology. HighlightsEnterococcus faecalis used in the generation of AD neurofibrillary epitopes in rat.Infection increases Alz-50, phospho-Serine 202 tau, and MAP2 expression.Infection by Enterococcus may play a role in early Alzheimer neurofibrillary changes.

Inhibition of p53 attenuates ischemic stress-induced activation of astrocytes.

In cerebral ischemia, studies of cell death have focused primarily on neurons, but recent work indicates that ischemia also causes damage to astrocytes. Activation of astrocytes is a typical brain response to stress stimuli and is evidenced by changes in cellular function and morphology, as well as upregulation of glial fibrillary acidic protein. The tumor-suppressor transcription factor p53 has recently been implicated as a mediator of ischemia-induced neuronal death, but very little is known about its role in the activation or the death of astrocytes. The present study investigated the role of p53 in astrocyte and neuronal toxicity using in-vitro and in-vivo ischemic stroke models. We showed that p53 is activated in ischemic brains and in oxygen-glucose deprivation (OGD)-induced cell death in neurons and astrocytes. Inhibition of p53 activity using either pifithrin-α or small interference RNA interference reduced OGD-induced cell death and pifithrin-α reversed OGD-induced impairment of glutamate uptake in astrocytes, suggesting that p53 might play a key role in mediating neurotoxicity and gliotoxicity in ischemic brain injury. This study shows that p53 is activated in astrocytes during ischemia and that inhibition of the activity of this molecule prevents not only OGD-induced neuronal and astrocytic death but also astrocyte activation and impaired glutamate uptake. These findings suggest that p53 may be a valuable therapeutic target in ischemic brain injury.

Cerebrospinal fluid (vascular endothelial growth factor) and serologic (recoverin) tumor markers for malignant glioma.

BACKGROUND: Clinically useful tumor markers have yet to be identified for malignant glioma. We report on two potential novel tumor markers, vascular endothelial growth factor (VEGF) and recoverin (protein A). VEGF is a highly specific endothelial cell activator that induces angiogenesis both in vivo and in vitro. Our study was designed to assess whether VEGF could be measured in the cerebrospinal fluid (CSF) of patients with cerebral neoplasms and used as a marker of particular tumors. We also studied serum recoverin levels in patients with various brain tumors and compared these to controls. Recoverin is a detectable serologic protein that is expressed in patients with cancer-associated retinopathy, a paraneoplastic syndrome. METHODS: In the VEGF arm, we used a solid-phase ELISA to determine the levels of VEGF. CSF samples from patients with anaplastic astrocytoma and glioblastoma multiforme (GBM) and with metastatic and nonastrocytic brain tumors were compared with nontumor control samples. In our recoverin study, an immunoenzymetric assay was used to measure the serum recoverin levels patients with glioma and compared with controls. RESULTS: In the VEGF arm, 89% of samples with malignant astrocytoma and 27% of nonastrocytoma samples had detectable levels of VEGF. VEGF was not detectable in normal CSF samples. The levels of VEGF were significantly higher in high-grade astrocytomas than in nonastrocytic tumors. Recoverin levels were 10-fold higher in patients with recurrent GBM relative to controls. In patients with low-grade glioma, anaplastic glioma, and GBM with no evidence of recurrence, a 3- to 5-fold increase was observed. CONCLUSIONS: VEGF is detectable in CSF and may be a potential marker for differentiating astrocytic from nonastrocytic tumors. Recoverin is detectable in serum and may be a useful glioma tumor marker, especially for recurrent active disease. These markers may have application for tumor diagnosis, surveillance, and treatment response.

Processing similarity does not improve metamemory: evidence against transfer-appropriate monitoring.

The transfer-appropriate monitoring (TAM) hypothesis of metamemory predicts that judgment of learning (JOL) accuracy should improve when conditions during JOLs closely match conditions of the memory test. The authors devised 5 types of delayed JOLs for paired associates and varied them along with the type of memory test (cued recall or recognition). If the TAM hypothesis is correct, JOL and test type should interact to influence metamemory. Contrary to TAM, metamemory accuracy did not improve when JOL and test conditions matched but instead tended to vary according to whether the answer was apparent at time of JOL. Memory test scores and JOL magnitude were both greater when the correct target was evident during JOLs. Overall, the results are largely consistent with a monitoring retrieval view of delayed JOLs and do not support TAM as a viable account of JOL accuracy.

High-Dose Chemotherapy with Peripheral Blood Stem Cell Support for Operable Locally Advanced Noninflammatory Carcinoma of the Breast.

The purpose of this study was to determine outcomes for patients with operable noninflammatory stage IIIA/B locally advanced breast cancer (LABC) with positive axillary lymph nodes receiving high-dose chemotherapy (HDC) with peripheral blood stem cell (PBSC) support. One hundred fifteen patients with LABC who were no evidence of disease (NED) after initial surgery received standard dose induction chemotherapy, chemotherapy for mobilization of PBSC, and high-dose cyclophosphamide, thiotepa, and carboplatin with PBSC support for adjuvant therapy. Following hematopoietic recovery, all patients were scheduled to receive radiation therapy and tamoxifen was administered if the primary tumor was estrogen receptor/progesterone receptor (ER/PR) positive. Eighty-eight percent of patients were admitted to the hospital following HDC for a median of 11 days (range 3-26) and 12% were treated entirely as outpatients. There was one treatment-related death (0.9%) from infection occurring on day 8 after HDC. Forty-four (38%) have relapsed at a median of 20 months (range 10-55) from diagnosis, 11 (10%) with local-regional and 33 (28%) with metastatic disease. The probabilities of overall (OS) and event-free survival (EFS) for all 115 patients at 3 years were 0.73 and 0.61, respectively, with a median follow-up of 42 months (range 10-89) from diagnosis. In univariate and multivariate analyses, no factors could be identified that were statistically predictive for OS or EFS. However, there were trends for patients with ER/PR-negative primary tumors to have worse OS (p = 0.16) and EFS (p = 0.10) than patients with ER/PR-positive tumors. This adjuvant combined modality strategy incorporating HDC is safe and compares favorably to historical studies of neoadjuvant or adjuvant treatment for LABC. Further attempts to improve outcomes of patients with LABC receiving HDC are warranted.

Consolidation-like effects in flashbulb memories: evidence from September 11, 2001.

After September 11, 2001, we distributed flashbulb memory questionnaires at 5 different dates: within 48 hr (T1) and at 1 week (T2), 1 month (T3), 3 months (T4), and 1 year (T5). We scored responses for self-reported memory (veracity unverified), memory accuracy (recollection-matched T1 response), and memory consistency (recollection-matched prior responses other than T1). Self-reported memory and subjective confidence remained near ceiling, although the accuracy declined. However, memories given a week or more after September 11 were consistent throughout. We hypothesize that flashbulb memories follow a consolidation-like process: Some details learned later are incorporated into the initial memory, and many others are discarded. After this process, memories stabilize. Therefore, the best predictor of flashbulb memories at long intervals is not the memory as initially reported but memories reported a week or more after the event.

Happiness of Asian Americans.

Past surveys found a positive relation between job satisfaction and socioeconomic status, with Asian Americans scoring low and African Americans and Euro-Americans scoring higher. As job satisfaction is a component of happiness, the question arises whether this relationship holds for happiness in general. Responses of a sample of 499 Asian Americans, 24,432 Euro-Americans, and 2,828 African Americans were analyzed. For both sexes, Asian Americans rated happiness significantly higher than African Americans. The rated happiness of Asian American and Euro-American men was not significantly different, but Asian-American women rated happiness significantly lower than Euro-American women. Mean differences were less than one point.