Protection against Amyloid-β Oligomer Neurotoxicity by Small Molecules with Antioxidative Properties: Potential for the Prevention of Alzheimer’s Disease Dementia

Soluble oligomeric assemblies of amyloid β-protein (Aβ), called Aβ oligomers (AβOs), have been recognized as primary pathogenetic factors in the molecular pathology of Alzheimer’s disease (AD). AβOs exert neurotoxicity and synaptotoxicity and play a critical role in the pathological progression of AD by aggravating oxidative and synaptic disturbances and tau abnormalities. As such, they are important therapeutic targets. From a therapeutic standpoint, it is not only important to clear AβOs or prevent their formation, it is also beneficial to reduce their neurotoxicity. In this regard, recent studies have reported that small molecules, most with antioxidative properties, show promise as therapeutic agents for reducing the neurotoxicity of AβOs. In this mini-review, we briefly review the significance of AβOs and oxidative stress in AD and summarize studies on small molecules with AβO-neurotoxicity-reducing effects. We also discuss mechanisms underlying the effects of these compounds against AβO neurotoxicity as well as their potential as drug candidates for the prevention and treatment of AD.

Immunogenic Proteins of Group B Streptococcus—Potential Antigens in Immunodiagnostic Assay for GBS Detection

Streptococcus agalactiae (Group B Streptococcus, GBS) is an opportunistic pathogen, which asymptomatically colonizes the gastrointestinal and genitourinary tract of up to one third of healthy adults. Nevertheless, GBS carriage in pregnant women may lead to several health issues in newborns causing life threatening infection, such as sepsis, pneumonia or meningitis. Recommended GBS screening in pregnant women significantly reduced morbidity and mortality in infants. Nevertheless, intrapartum antibiotic prophylaxis, recommended following the detection of carriage or in case of lack of a carriage test result for pregnant women who demonstrate certain risk factors, led to the expansion of the adverse phenomenon of bacterial resistance to antibiotics. In our paper, we reviewed some immunogenic GBS proteins, i.e., Alp family proteins, β protein, Lmb, Sip, BibA, FsbA, ScpB, enolase, elongation factor Tu, IMPDH, and GroEL, which possess features characteristic of good candidates for immunodiagnostic assays for GBS carriage detection, such as immunoreactivity and specificity. We assume that they can be used as an alternative diagnostic method to the presently recommended bacteriological cultivation and MALDI.

The Levels of Amyloid β-Protein and P181 in Peripheral Blood of Patients with Alzheimer’s Disease Combined with Helicobacter pylori Infection and Their Clinical Significance

Objective. To analyze the levels of amyloid β-protein and P181 in peripheral blood of patients with Alzheimer’s disease combined with Helicobacter pylori infection and their clinical significance. Method. From January 2019 to June 2020, 59 patients were enrolled in this experiment including the AD group with 27 patients and the normal control group with 32 patients. The patients were divided into two groups: Alzheimer’s disease (AD) group ( n = 27 ) and control group ( n = 32 ), collecting the general data of patients, analyzing the diagnostic specificity and sensitivity of serum p-tau181 and Aβ42 and their influence on prognosis, and comparing the serum Aβ42 and p-tau181 concentrations for different HP infection degrees. Result. Single diagnostic sensitivity of Aβ42, p-tau181, and Aβ42 combined p-tau181 was 0.863, 0.854, and 0.972, respectively, and their specificity was 0.048, 0.206, and 0.305, respectively. Compared with the single diagnosis of serum Aβ42 and p-tau181, the combined diagnosis has higher sensitivity and specificity ( P < 0.05 ); age, years of education, serum Aβ42, and p-tau181 are factors affecting the prognosis of patients with Alzheimer’s disease combined with Helicobacter pylori infection; the concentration of Aβ42 in the control group was higher than that in the AD group, there was a statistical difference in the Aβ42 concentration between the two groups ( P < 0.05 ), and there was no statistical difference in the concentration of p-tau181 between the two groups ( P > 0.05 ); the HP positive infection rate of the AD group and the control group was 63.0% and 35.7%, respectively. The HP negative infection rate of the AD group and the control group was 37.0% and 64.3%, respectively. Compared with the control group, the positive rate of HP in the AD group was higher, and the difference was statistically significant ( P < 0.05 ); compared with HP-negative patients, HP-positive patients had a higher Aβ42 concentration, and the difference was statistically significant ( P < 0.05 ). The concentration of p-tau181 in the two groups was not statistically significant ( P > 0.05 ); Aβ42 gradually increases with increasing HP infection degree, and there are significant differences in serum Aβ42 levels between different degrees of infection. However, the level of serum p-tau181 does not change significantly with the increase of infection. Conclusion. There are significant alterations in the expression levels of Aβ42 and p-tau181 in peripheral blood of AD patients, and the levels of Aβ42 are related to HP infection; Aβ42 and p-tau181 are potential biomarkers for AD diagnosis and treatment.

Amyloid β protein negatively regulates human platelet activation induced by thrombin receptor-activating protein

Amyloid β protein deposition in cerebral vessels, a characteristic of Alzheimer's disease, is a risk factor for intracerebral hemorrhage. Amyloid β protein directly modulates human platelet function; however, the exact mechanism of action is unclear. Therefore, we investigated the effects of amyloid β protein on human platelet activation using an aggregometer with laser scattering. Amyloid β protein decreased platelet aggregation induced by thrombin receptor-activating protein, but not by collagen and ADP. Amyloid β protein also suppressed platelet aggregation induced by SCP0237 and A3227. Platelet-derived growth factor-AB secretion and phosphorylated-heat shock protein 27 release by thrombin receptor-activating protein were inhibited by amyloid β protein. Additionally, thrombin receptor-activating protein-induced phosphorylation of JNK and p38 MAP kinase was reduced by amyloid β protein. Collectively, our results strongly suggest that amyloid β protein negatively regulates protease-activated receptor-elicited human platelet activation. These findings may indicate a cause of intracerebral hemorrhage due to amyloid β protein.

Mitochondrial Membrane Potential Influences Amyloid-β Protein Precursor Localization and Amyloid-β Secretion

Background: Amyloid-β (Aβ), which derives from the amyloid-β protein precursor (AβPP), forms plaques and serves as a fluid biomarker in Alzheimer’s disease (AD). How Aβ forms from AβPP is known, but questions relating to AβPP and Aβ biology remain unanswered. AD patients show mitochondrial dysfunction, and an Aβ/AβPP mitochondria relationship exists. Objective: We considered how mitochondrial biology may impact AβPP and Aβ biology. Methods: SH-SY5Y cells were transfected AβPP constructs. After treatment with FCCP (uncoupler), Oligomycin (ATP synthase inhibitor), or starvation Aβ levels were measured. β-secretase (BACE1) expression was measured. Mitochondrial localized full-length AβPP was also measured. All parameters listed were measured in ρ0 cells on an SH-SY5Y background. iPSC derived neurons were also used to verify key results. Results: We showed that mitochondrial depolarization routes AβPP to, while hyperpolarization routes AβPP away from, the organelle. Mitochondrial AβPP and cell Aβ secretion inversely correlate, as cells with more mitochondrial AβPP secrete less Aβ, and cells with less mitochondrial AβPP secrete more Aβ. An inverse relationship between secreted/extracellular Aβ and intracellular Aβ was observed. Conclusion: Our findings indicate mitochondrial function alters AβPP localization and suggest enhanced mitochondrial activity promote Aβ secretion while depressed mitochondrial activity minimize Aβ secretion. Our data complement other studies that indicate a mitochondrial, AβPP, and Aβ nexus, and could help explain why cerebrospinal fluid Aβ is lower in those with AD. Our data further suggest Aβ secretion could serve as a biomarker of cell or tissue mitochondrial function.