Therapeutic Potential of Ferulic Acid in Alzheimer's Disease

Alzheimer's Disease (AD) is one of the most important neurodegenerative diseases and it covers 60% of whole dementia cases. AD is a constantly progressing neurodegenerative disease as a result of the production of β-amyloid (Aβ) protein and the accumulation of hyper-phosphorylated Tau protein; it causes breakages in the synaptic bonds and neuronal deaths to a large extent. Millions of people worldwide suffer from AD because there is no definitive drug for disease prevention, treatment or slowdown. Over the last decade, multiple target applications have been developed for AD treatments. These targets include Aβ accumulations, hyper-phosphorylated Tau proteins, mitochondrial dysfunction, and oxidative stress resulting in toxicity. Various natural or semisynthetic antioxidant formulations have been shown to protect brain cells from Aβ induced toxicity and provide promising potentials for AD treatment. Ferulic acid (FA), a high-capacity antioxidant molecule, is naturally synthesized from certain plants. FA has been shown to have different substantial biological properties, such as anticancer, antidiabetic, antimicrobial, anti-inflammatory, hepatoprotective, and cardioprotective actions, etc. Furthermore, FA exerted neuroprotection via preventing Aβ-fibril formation, acting as an anti-inflammatory agent, and inhibiting free radical generation and acetylcholinesterase (AChE) enzyme activity. In this review, we present key biological roles of FA and several FA derivatives in Aβ-induced neurotoxicity, protection against free radical attacks, and enzyme inhibitions and describe them as possible therapeutic agents for the treatment of AD.

Sensitive Electrochemical Detection of Phosphorylated-Tau Threonine 231 in Human Serum Using Interdigitated Wave-Shaped Electrode

The development of an electrochemical biosensor for the detection of phosphorylated-tau threonine 231 (p-tau231), a biomarker of Alzheimer’s disease (AD), has yet to be achieved. Therefore, in this study, we developed a simple, small size, cheap, and sensitive electrochemical biosensor based on an interdigitated wave-shaped electrode via an activated self-assembled monolayer to preserve a specific anti–p-tau231 antibody (IWE/SAM/EDC-NHS/anti–p-tau231). Detection of p-tau231 in human serum (HS) using the biosensor was undertaken using electrochemical impedance spectroscopy (EIS). The change in charge-transfer resistance (Rct) in the EIS analysis of the biosensor indicated the detection of p-tau231 in HS within a wide linear range of detection (10−4–101 ng mL−1), and a low limit of detection (140 pg mL−1). This lower limit is less than the detection level of p-tau231 in cerebrospinal fluid (CSF) (700 pg mL−1) of AD patients and the level of CSF p-tau231 of patients with mild cognitive impairment (501 pg mL−1), demonstrating the possibility of using the biosensor in detection of p-tau231 at early stage AD. A high binding affinity and low dissociation constant (Kd) between anti–p-tau231 and p-tau231 in HS was demonstrated by using a biosensor and Kd was 7.6 pM, demonstrating the high specific detection of p-tau231 by the biosensor. The good selectivity of the biosensor for the detection of p-tau231 with differential analytes was also examined in this study.

Differences between plasma and CSF p-tau181 and p-tau231 in early Alzheimer s disease

Plasma phosphorylated tau species have been recently proposed as peripheral markers of Alzheimer s disease pathology. In this cross-sectional study incuding ninety-one subjects, plasma p-tau181 and p-tau231 levels were elevated in the early symptomatic stages of AD, with similar levels than those of CSF. Plasma p-tau231 and p-tau181 were strongly related to CSF tau and amyloid and exhibited a high accuracy, close to CSF p-tau231 and p-tau181, to identify AD already in the early stage of the disease. The findings might support the use as diagnostic and prognostic peripheral AD biomarkers in both research and clinical settings.

Biologic TNF-α inhibitors reduce microgliosis, neuronal loss, and tau phosphorylation in a transgenic mouse model of tauopathy

Background Tumor necrosis factor-α (TNF-α) plays a central role in Alzheimer’s disease (AD) pathology, making biologic TNF-α inhibitors (TNFIs), including etanercept, viable therapeutics for AD. The protective effects of biologic TNFIs on AD hallmark pathology (Aβ deposition and tau pathology) have been demonstrated. However, the effects of biologic TNFIs on Aβ-independent tau pathology have not been reported. Existing biologic TNFIs do not cross the blood–brain barrier (BBB), therefore we engineered a BBB-penetrating biologic TNFI by fusing the extracellular domain of the type-II human TNF-α receptor (TNFR) to a transferrin receptor antibody (TfRMAb) that ferries the TNFR into the brain via receptor-mediated transcytosis. The present study aimed to investigate the effects of TfRMAb-TNFR (BBB-penetrating TNFI) and etanercept (non-BBB-penetrating TNFI) in the PS19 transgenic mouse model of tauopathy. Methods Six-month-old male and female PS19 mice were injected intraperitoneally with saline (n = 12), TfRMAb-TNFR (1.75 mg/kg, n = 10) or etanercept (0.875 mg/kg, equimolar dose of TNFR, n = 10) 3 days/week for 8 weeks. Age-matched littermate wild-type mice served as additional controls. Blood was collected at baseline and 8 weeks for a complete blood count. Locomotion hyperactivity was assessed by the open-field paradigm. Brains were examined for phosphorylated tau lesions (Ser202, Thr205), microgliosis, and neuronal health. The plasma pharmacokinetics were evaluated following a single intraperitoneal injection of 0.875 mg/kg etanercept or 1.75 mg/kg TfRMAb-TNFR or 1.75 mg/kg chronic TfRMAb-TNFR dosing for 4 weeks. Results Etanercept significantly reduced phosphorylated tau and microgliosis in the PS19 mouse brains of both sexes, while TfRMAb-TNFR significantly reduced these parameters in the female PS19 mice. Both TfRMAb-TNFR and etanercept treatment improved neuronal health by significantly increasing PSD95 expression and attenuating hippocampal neuron loss in the PS19 mice. The locomotion hyperactivity in the male PS19 mice was suppressed by chronic etanercept treatment. Equimolar dosing resulted in eightfold lower plasma exposure of the TfRMAb-TNFR compared with etanercept. The hematological profiles remained largely stable following chronic biologic TNFI dosing except for a significant increase in platelets with etanercept. Conclusion Both TfRMAb-TNFR (BBB-penetrating) and non-BBB-penetrating (etanercept) biologic TNFIs showed therapeutic effects in the PS19 mouse model of tauopathy.