Current Alzheimer Research - Volume 16, Issue 10, 2019

Albeit cholinergic depletion remains the key event in Alzheimer’s Disease (AD), recent information describes stronger links between monoamines (trace amines, catecholamines, histamine, serotonin, and melatonin) and AD than those known in the past century. Therefore, new drug design strategies focus efforts to translate the scope on these topics and to offer new drugs which can be applied as therapeutic tools in AD. In the present work, we reviewed the state-of-art regarding genetic, neuropathology and neurochemistry of AD involving monoamine systems. Then, we compiled the effects of monoamines found in the brain of mammals as well as the reported effects of their derivatives and some structure-activity relationships. Recent derivatives have triggered exciting effects and pharmacokinetic properties in both murine models and humans. In some cases, the mechanism of action is clear, essentially through the interaction on G-protein-coupled receptors as revised in this manuscript. Additional mechanisms are inhibition of enzymes for their biotransformation, regulation of free-radicals in the central nervous system and others for the effects on Tau phosphorylation or amyloid-beta accumulation. All these data make the monoamines and their derivatives attractive potential elements for AD therapy.

The most common type of dementia found in the elderly population is Alzheimer’s disease. The disease not only impacts the patients and their families but also the society therefore, the main focus of researchers is to search new bioactive materials for treating AD. The marine environment is a rich source of functional ingredients and to date, we can find sufficient research relating to anti- Alzheimer’s compounds isolated from marine environment. Therefore, this review focuses on the anti- Alzheimer’s material from marine bio-resources and then expounds on the anti-Alzheimer’s compounds from marine seaweed, marine animal and marine microorganisms. Moreover, because of the complexity of the disease, different hypothesizes have been elaborated and active compounds have been isolated to inhibit different stages of pathophysiological mechanisms. Sulfated polysaccharides, glycoprotein, and enzymatic hydrolysates from marine seaweeds, peptides, dietary omega-3 polyunsaturated fatty acids and skeletal polysaccharide from marine animals and secondary metabolites from marine microorganism are summarized in this review under the anti-Alzheimer’s compounds from the marine.

Alzheimer’s Disease (AD) is an age-dependent neurodegenerative disorder, the most common type of dementia that is clinically characterized by the presence of beta-amyloid (Aβ) extracellularly and intraneuronal tau protein tangles that eventually leads to the onset of memory and cognition impairment, development of psychiatric symptoms and behavioral disorders that affect basic daily activities. Current treatment approved by the U.S Food and Drug Administration (FDA) for AD is mainly focused on the symptoms but not on the pathogenesis of the disease. Recently, receptor-interacting protein kinase 1 (RIPK1) has been identified as a key component in the pathogenesis of AD through necroptosis. Furthermore, genetic and pharmacological suppression of RIPK1 has been shown to revert the phenotype of AD and its mediating pathway is yet to be deciphered. This review is aimed to provide an overview of the pathogenesis and current treatment of AD with the involvement of autophagy as well as providing a novel insight into RIPK1 in reverting the progression of AD, probably through an autophagy machinery.

Background: In recent years, several reviews have addressed the effectiveness of dance therapy in dementia, healthy older adults, or the elderly in general. However, reviews regarding the effect of this therapy exclusively on patients diagnosed with Alzheimer’s disease have not been found. Objective: The purpose of this study is to review the available literature describing clinical trials which explore the effects of dancing on psychological and physical outcomes, functionality, cognitive function, and quality of life in patients diagnosed with Alzheimer’s disease. In addition, this review aims to assess the quality of studies that perform dance therapy interventions in these patients. Methods: This study is a systematic review of randomized and non-randomized clinical trials regarding the effect of intervention including a dancing activity in people diagnosed with Alzheimer's disease. Results: In total, the evidence for this review rests on 12 studies with a total of 349 participants. The findings of this mini-review confirm the positive effect of dance therapy on physical and cognitive function, functionality, psychological outcomes, and quality of life in people with Alzheimer's disease. Conclusion: Most of the studies implementing dance as part of the therapeutic treatment has shown to improve or slow the worsening in the quality of life of patients with Alzheimer's disease and their caregivers. Future research focused on these patients should use a more exhaustive methodology and make a more detailed description of these kind of interventions.

Background: Amyloid-β42 oligomers (Aβ42O), the proximate effectors of neurotoxicity observed in Alzheimer’s disease (AD), can induce mitochondrial oxidative stress and impair mitochondrial function besides causing mitochondrial DNA (mtDNA) damage. Aβ42O also regulate the proliferative and differentiative properties of stem cells. Objective: We aimed to study whether Aβ42O-induced mtDNA damage is involved in the regulation of stem cell differentiation. Method: Human iPSCs-derived neural stem cell (NSC) was applied to investigate the effect of Aβ42O on reactive oxygen species (ROS) production and DNA damage using mitoSOX staining and long-range PCR lesion assay, respectively. mtDNA repair activity was measured by non-homologous end joining (NHEJ) in vitro assay using mitochondria isolates and the expression and localization of NHEJ components were determined by Western blot and immunofluorescence assay. The expressions of Tuj-1 and GFAP, detected by immunofluorescence and qPCR, respectively, were examined as an index of neurons and astrocytes production. Results: We show that in NSC Aβ42O treatment induces ROS production and mtDNA damage and impairs DNA end joining activity. NHEJ components, such as Ku70/80, DNA-PKcs, and XRCC4, are localized in mitochondria and silencing of XRCC4 significantly exacerbates the effect of Aβ42O on mtDNA integrity. On the contrary, pre-treatment with Phytic Acid (IP6), which specifically stimulates DNA-PK-dependent end-joining, inhibits Aβ42O-induced mtDNA damage and neuronal differentiation alteration. Conclusion: Aβ42O-induced mtDNA repair impairment may change cell fate thus shifting human NSC differentiation toward an astrocytic lineage. Repair stimulation counteracts Aβ42O neurotoxicity, suggesting mtDNA repair pathway as a potential target for the treatment of neurodegenerative disorders like AD.

Background: There is an increasing interest on Cognitive Impairment (CI) in patients with type 2 diabetes mellitus (T2DM), but evidence is conflicting regarding the association between CI and glycemic control. Objective: The present study aimed to estimate the prevalence of CI in patients with T2DM from northern rural China in order to determine whether cognitive dysfunction is related to glycemic control. Methods: First, we conducted a study with a cross-sectional design. We performed cluster random sampling of 1848 residents who were aged 60 years or older and lived in the countryside in China. All eligible participants with and without T2DM were interviewed and screened for cognitive function status. Diagnoses for dementia and Cognitive Impairment No Dementia (CIND) were based on the standard criteria. Second, on the basis of the results of the cross-sectional survey, we conducted a case-control study. In the T2DM group, we identified cases of T2DM with Cognitive Impairment (T2DM-CI), as well as cases of T2DM with normal cognition (T2DM-NC) to be used as controls. The effects of specific diabetes-related variables were examined. After matching for sex, age, and education level in the T2DM-CI and T2DM-NC groups, multivariate logistic regression analyses were performed to evaluate risk factors for T2DM-CI. Results: In the cross-sectional study, the prevalence of T2DM with CIND and dementia were 28.3% (95% CI: 23.5-33.2) and 9.5% (95% CI: 6.3-12.6), respectively. Compared with subjects without DM, the prevalence of CI in T2DM patients was more frequent than the prevalence of CI in the general population in almost every age group. In the case-control study, the multivariate logistic regression analyses showed that variables, including duration from diabetes onset, glycosylated hemoglobin A1c level (HbA1c), and severe hypoglycemia history, were significantly associated with an increased risk of CI in patients with T2DM (odds ratios [ORs] [95%CIs]: 1.67 [1.03-2.70], 1.40 [1.15-1.72], and 2.72 [1.02- 7.21], respectively [P <0.05]). Conclusion: The present study demonstrates a high prevalence of CI in patients with T2DM among the elderly population of rural China. Glycemic control, including HbA1c and exposure to severe hypoglycemia, affected cognitive function in patients with T2DM.

Background: Cholinesterase inhibitors are routinely applied in the treatment of Alzheimer’s disease, and seeking new cholinesterase inhibitors is a priority. Objectives: Twenty seven compounds were compared, including ones not previously tested. An attempt was undertaken to precisely describe the role of alcohol in the inhibitory activity. This paper underlines the role of a “false positive” blank sample in the routine analysis. Methods: The inhibition of cholinesterase was measured using Ellman’s colorimetric method with a few modifications designed by the authors (including the “false-positive” effect). The inhibitory role of ethanol and methanol was also carefully evaluated. The present and past results were compared taking the source of enzyme and alcohol content into consideration. Results: For the first time, new inhibitors were identified, namely: methyl jasmonate, 1R-(−)-nopol ((anti-acetyl-(AChE) and butyrylcholinesterase (BChE) activity)) and 1,4-cineole, allo-aromadendrene, nerolidol, β-ionone, and (R)-(+)-pulegone (anti-BChE activity). Oleanolic acid and (+)-β-citronellene (not previously studied) proved to be inefficient inhibitors. For a number of well-known inhibitors (such as nerol, (−)-menthol, (+)-menthol, isoborneol, (−)-bornyl acetate, limonene, α-pinene, β-pinene, α- ionone, and eugenol) some serious discrepancies were observed between our findings and the results of previous studies. Ethanol and methanol showed no anti-AChE activity up to 0.29% (v/v) and 0.23% (v/v), respectively. Similarly, ethanol up to 0.33% (v/v) and methanol up to 0.29% (v/v) did not inhibit the activity of BChE. Conclusion: It can be stated that the impact of alcohol should be precisely determined and that blank “false-positive” samples should be processed together with test samples. Furthermore, the effect of the enzyme origin on the result of this test must be taken into consideration.