Discovery and Characterization of Multi-Target Directed Ligands as Inhibitors of Amyloid-β Aggregation and Regulators of Alzheimer\u27s Disease

Alzheimer\u27s disease (AD) is the most common neurodegenerative disease in the world. As the disease advances, symptoms include confusion, language skill breakdown, and long term memory loss - and culminate in death. Existing therapies for AD provide symptomatic benefits but cannot halt or slow the disease pathogenesis. Increasing evidence reveals the multi-factorial nature of AD. Numerous factors, including amyloid-β (Aβ) aggregation, calcium homeostasis dysregulation, and oxidative stress, contribute to disease development and interplay with each other. Therefore, multi-target directed ligands (MTDLs) may present an effective AD treatment. Among all factors, Aβ aggregation is suggested to play the most crucial role. Compounds containing aromatic centers have been proposed as effective Aβ aggregation inhibitors; however, the influence of functional groups on the aromatic ring and the number of aromatic structures has not been comprehensively explored. Furthermore, the addition of functional groups presents an opportunity to endow therapeutic compounds with additional properties that can target other pathogenic pathways. The work presented here examines three potential MTDLs for AD. First, experimentation investigates inhibitory capabilities of a group of FDA-approved calcium channel blockers, dihydropyridines, in Aβ aggregation. Results identify all selected dihydropyridines as inhibiters of Aβ aggregation that exhibit distinct mechanisms. These mechanistic differences alter the morphology of Aβ aggregates, which may be related to cytotoxicity. In addition, naphthalimide analogs were identified as novel inhibitors of Aβ aggregation. Several naphthalimide analogs with distinct lengths of the carbon linker were tested, and those with a two-carbon linker showed a significant inhibition by delaying the onset of aggregation. By introducing hydroxyl groups on the phenyl ring, the inhibitory capability of this compound was further enhanced and antioxidant activity was endowed. Finally, anthocyanidins, a group of polyphenols, were investigated for their ability to both intervene with Aβ aggregation and perform as antioxidants. Results indicate that anthocyanidins exhibit potent antioxidant activities, and inhibit the earlier stages of Aβ aggregation. Furthermore, the inhibitory capability is related to the number of hydroxyl groups. Together, this study provides insight into the effective properties of dihydropyridines, naphthalimides, and anthocyanidins as novel promising MTDLs for the pathogenesis in AD

A Dual Pathogenic Mechanism Links Tau Acetylation to Sporadic Tauopathy

Tau acetylation has recently emerged as a dominant post-translational modification (PTM) in Alzheimer’s disease (AD) and related tauopathies. Mass spectrometry studies indicate that tau acetylation sites cluster within the microtubule (MT)-binding region (MTBR), suggesting acetylation could regulate both normal and pathological tau functions. Here, we combined biochemical and cell-based approaches to uncover a dual pathogenic mechanism mediated by tau acetylation. We show that acetylation specifically at residues K280/K281 impairs tau-mediated MT stabilization, and enhances the formation of fibrillar tau aggregates, highlighting both loss and gain of tau function. Full-length acetylation-mimic tau showed increased propensity to undergo seed-dependent aggregation, revealing a potential role for tau acetylation in the propagation of tau pathology. We also demonstrate that methylene blue, a reported tau aggregation inhibitor, modulates tau acetylation, a novel mechanism of action for this class of compounds. Our study identifies a potential “two-hit” mechanism in which tau acetylation disengages tau from MTs and also promotes tau aggregation. Thus, therapeutic approaches to limit tau K280/K281 acetylation could simultaneously restore MT stability and ameliorate tau pathology in AD and related tauopathies

The Deacetylase HDAC6 Mediates Endogenous Neuritic Tau Pathology

The initiating events that promote tau mislocalization and pathology in Alzheimer's disease (AD) are not well defined, partly because of the lack of endogenous models that recapitulate tau dysfunction. We exposed wild-type neurons to a neuroinflammatory trigger and examined the effect on endogenous tau. We found that tau re-localized and accumulated within pathological neuritic foci, or beads, comprised of mostly hypo-phosphorylated, acetylated, and oligomeric tau. These structures were detected in aged wild-type mice and were enhanced in response to neuroinflammation in vivo, highlighting a previously undescribed endogenous age-related tau pathology. Strikingly, deletion or inhibition of the cytoplasmic shuttling factor HDAC6 suppressed neuritic tau bead formation in neurons and mice. Using mass spectrometry-based profiling, we identified a single neuroinflammatory factor, the metalloproteinase MMP-9, as a mediator of neuritic tau beading. Thus, our study uncovers a link between neuroinflammation and neuritic tau beading as a potential early-stage pathogenic mechanism in AD

Power Factor Corrector with Bridgeless Flyback Converter for DC Loads Applications

Since power systems with a DC distribution method has many advantages, such as conversion efficiency increase of about 5⁻10%, cost reducing by about 15⁻20% and so on, the AC distribution power system will be replaced by a DC distribution one. This paper presents a DC load power system for a DC distribution application. The proposed power system includes two converters: DC/DC converter with battery source and power factor corrector (PFC) with a line source to increase the reliability of the power system when renewable energy or energy storage equipment are adopted. The proposed PFC adopts a bridgeless flyback converter to achieve power factor correction for supplying power to DC loads. When the bridgeless flyback converter is used to achieve PFC, it needs two transformers to process positive and negative half periods, respectively. In order to increase conversion efficiency, the flyback one can add two sets of the active clamp circuit to recover energies stored in leakage inductances of transformers in the converter. Therefore, the proposed bridgeless flyback converter can not only integrate two transformers into a single transformer, but also share a clamp capacitor to achieve energy recovery of leakage inductances and to operate switches with zero-voltage switching (ZVS) at the turn-on transition. With this approach, the proposed converter can increase conversion efficiency and decrease component counts, where it results in a higher conversion efficiency, lower cost, easier design and so on. Finally, a prototype with a universal input voltage source (AC 90⁻265 V) under output voltage of 48 V and maximum output power of 300 W has been implemented to verify the feasibility of the proposed bridgeless flyback converter. Furthermore, the proposed power system can be operated at different cases among load power PL, output power PDC1 of DC/DC converter and output power PDC2 of the proposed PFC for supplying power to DC loads

Association between Periodontal Disease and Subsequent Sjögren’s Syndrome: A Nationwide Population-Based Cohort Study

Xerostomia (dry mouth) is the cardinal symptom of Sjögren’s syndrome (SS), which is an autoimmune disease involving the exocrine glands and other organs. Xerostomia may predispose patients to periodontal disease (PD) and an association between SS and PD has been reported. This association may be bidirectional; therefore, we conducted this study to investigate the risk of SS in patients with PD using data from the National Health Insurance Research Database of Taiwan. A total of 135,190 patients were enrolled in our analysis. In all, 27,041 patients with PD were matched by gender, age, insured region, urbanization and income, with cases and controls in a 1:4 ratio. Both groups were followed and the risks of SS were calculated by Cox proportional hazards regression. Finally, 3292 (2.4%) patients had newly diagnosed SS. Patients with PD had a significantly higher risk of subsequent SS (903 (3.3%) vs. 2389 (2.2%), adjusted hazard 1.47, 95% confidence interval: 1.36–1.59). In conclusion, patients with PD had an approximately 50% increased risk of subsequent SS. Physicians should be aware of the symptoms and signs of SS in patients with PD

Increased Risk of Ulcerative Colitis in Patients with Periodontal Disease: A Nationwide Population-Based Cohort Study

Both periodontal disease (PD) and inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are important diseases of the alimentary tract. Microbiome and immune-mediated inflammatory processes play important roles in these diseases. An association between PD and IBD may exist. This study investigated the risk of IBD in patients with PD. This study used data from the National Health Insurance Research Database of Taiwan from 1996 to 2013. A total of 27,041 patients with PD were enrolled as a study group, and 108,149 patients without PD were selected as the control group after matching by gender, age, insured region, urbanization, and income with a 1:4 ratio. Cox proportional hazards regression was used to calculate the risk of IBD. Of the 135,190 participants enrolled in this study, 5392 (4%) with newly diagnosed IBD were identified. The overall incidence of subsequent IBD was similar in both groups (3.8% vs. 4%, adjusted hazard ratio (aHR) = 1.01, 95% confidence interval (CI): 0.94⁻1.08). However, an increased risk of UC in the PD group was found after adjusting confounding factors (aHR: 1.56, 95% CI: 1.13⁻2.15; p < 0.05). This study demonstrated that patients with PD had approximately one-half higher risk of subsequent UC. Further studies are warranted to elucidate the relationship between PD and UC