Oxidative Stress and Beta Amyloid in Alzheimer’s Disease. Which Comes First: The Chicken or the Egg?

The pathogenesis of Alzheimer’s disease involves β amyloid (Aβ) accumulation known to induce synaptic dysfunction and neurodegeneration. The brain’s vulnerability to oxidative stress (OS) is considered a crucial detrimental factor in Alzheimer’s disease. OS and Aβ are linked to each other because Aβ induces OS, and OS increases the Aβ deposition. Thus, the answer to the question “which comes first: the chicken or the egg?” remains extremely difficult. In any case, the evidence for the primary occurrence of oxidative stress in AD is attractive. Thus, evidence indicates that a long period of gradual oxidative damage accumulation precedes and results in the appearance of clinical and pathological AD symptoms, including Aβ deposition, neurofibrillary tangle formation, metabolic dysfunction, and cognitive decline. Moreover, oxidative stress plays a crucial role in the pathogenesis of many risk factors for AD. Alzheimer’s disease begins many years before its symptoms, and antioxidant treatment can be an important therapeutic target for attacking the disease.

Serum Amyloid Biomarkers, Tau Protein and YKL-40 Utility in Detection, Differential Diagnosing, and Monitoring of Dementia

Introduction: The diagnosis and treatment of dementia is one of the greatest challenges in contemporary health care. The widespread use of dementia biomarkers would improve the quality of life of patients and reduce the economic costs of the disease. The aim of the study was to evaluate the usefulness of proteins related to the Alzheimer's disease pathogenesis—amyloid beta isoform (Aβ) and total tau protein (t-tau), as well as the quite recently discovered marker YKL-40 in the most common types of dementia.Methods: 60 dementia (AD—Alzheimer's disease, VaD—vascular dementia, MxD—mixed dementia) and 20 cognitively normal subjects over 60 years old were examined. Subjects with dementia of etiology different than AD or VaD and with neoplastic or chronic inflammatory diseases were excluded. Concentrations of Aβ40, Aβ42, t-tau, and YKL-40 were measured in serum using ELISA kits on admission and after 4 weeks of inpatient treatment. ANOVA and Tukey's test or Dunn's test were used to perform comparison tests between groups. Correlations were measured using Pearson's coefficient. Biomarker diagnostic utility was assessed with ROC analysis.Results: YKL-40 differentiates between cognitively normal and mild dementia patients with 85% sensitivity and specificity and t-tau with 72% sensitivity and 70% specificity. YKL-40 and t-tau concentrations correlate with each other and with the severity of clinically observed cognitive decline.Conclusions: YKL-40 is a sensitive and specific biomarker of early dementia and, to a lesser extent, of dementia progression, however, many comorbidities may influence its levels. In such conditions, less specific but still reliable t-tau may serve as an alternative marker. Obtained results did not confirm the diagnostic utility of amyloid biomarkers.

fMRI Investigation of Semantic Lexical Processing in Healthy Control and Alzheimer’s Disease Subjects Using Naming Task: A Preliminary Study

For decades, scientists have been trying to solve the problem of dementia, with no cure currently available. Semantic–lexical impairment is well established as the early critical sign of dementia, although there are still gaps in knowledge that must be investigated. In this study, we used fMRI to observe the neural activity of 31 subjects, including 16 HC (Healthy Control) and 15 AD (Alzheimer’s Disease), who participated in the naming task. The neuropsychology profile of HC (Healthy Control) and AD (Alzheimer’s Disease) are discussed in this study. The involvement of FG (Fusiform Gyrus) and IFG (Inferior Frontal Gyrus) shows dominant activation in both of the groups. We observed a decrease in neural activity in the AD group, resulting in semantic deficit problems in this preliminary study. Furthermore, ROI analysis was performed and revealed both hyperactivation and hypoactivation in the AD group. The compensatory mechanism demonstrated during the task, due to the effort required to identify an animal’s name, represents the character profile of AD.

INCREASED EXPRESSION OF SOLUBLE INACTIVE ADAM10 IN PATIENTS WITH ALZHEIMER’S DISEASE AND TYPE 2 DIABETES MELLITUS

Background: DM2 (type 2 diabetes mellitus) can lead to higher risk of developing AD (Alzheimer’s disease). Previous results show that soluble inactive ADAM10 (A Disintegrin And Metalloprotease 10) plasma levels are increased in AD. Objectives: To compare plasma ADAM10 levels between cognitively healthy participants, patients with AD and with the concomitant presence of AD and DM2. Methods: Plasma samples from 36 individuals aged 60 years or more were analyzed, divided into 4 groups: Cognitively and metabolically preserved, AD, DM2 and concomitant presence of AD and DM2. Blood was collected and plasma was separated by centrifugation. The total protein concentration was determined using the Pierce BCA method. ADAM10 levels were determined by SDS-PAGE analysis followed by western blotting. Human serum albumin levels were used as endogen control. Results: Both AD and DM patients had increased plasma ADAM10 levels compared to control participants and these levels were also higher in patients with both diseases. These preliminary results indicate that changes in the insulin pathway may be related to changes in plasma ADAM10 levels, contributing to the development of AD. Conclusions: This study can contribute to the understanding of the biology of the disease itself, as well as the treatment of this type of dementia, also observing the metabolic state of patients.

Proteostasis regulation by the ubiquitin system

Cells have developed an evolutionary obligation to survey and maintain proteome fidelity and avoid the possible toxic consequences of protein misfolding and aggregation. Disturbances to protein homoeostasis (proteostasis) can result in severe cellular phenotypes and are closely linked with the accumulation of microscopically visible deposits of aggregated proteins. These include inclusion bodies found in AD (Alzheimer's disease), HD (Huntington's disease) and ALS (amyotrophic lateral sclerosis) patient neurons. Protein aggregation is intimately linked with the ubiquitin and ubiquitin-like post-translational modifier system, which manages cellular protein folding stress and promotes the restoration of proteostasis. This is achieved in large part through the action of the UPS (ubiquitin–proteasome system), which is responsible for directing the proteasomal destruction of misfolded and damaged proteins tagged with ubiquitin chains. There are other less well understood ways in which ubiquitin family members can help to maintain proteostasis that complement, but are independent of, the UPS. This article discusses our current understanding of how the ubiquitin family regulates the protein misfolding pathways that threaten proteome fidelity, and how this is achieved by the key players in this process.

From epidemiology to pathophysiology: what about caffeine in Alzheimer's disease?

AD (Alzheimer's disease) is the most prevalent form of dementia in the aged population. Definitive diagnosis of AD is based on the presence of senile plaques and neurofibrillary tangles that are identified in post-mortem brain specimens. A third pathological component is inflammation. AD results from multiple genetic and environmental risk factors. Among other factors, epidemiological studies report beneficial effects of caffeine, a non-selective antagonist of adenosine receptors. In the present review, we discuss the impact of caffeine and the adenosinergic system in AD pathology as well as consequences in terms of pathology and therapeutics.

Lysosome and calcium dysregulation in Alzheimer's disease: partners in crime

Early-onset FAD (familial Alzheimer's disease) is caused by mutations of PS1 (presenilin 1), PS2 (presenilin 2) and APP (amyloid precursor protein). Beyond the effects of PS1 mutations on proteolytic functions of the γ-secretase complex, mutant or deficient PS1 disrupts lysosomal function and Ca2+ homoeostasis, both of which are considered strong pathogenic factors in FAD. Loss of PS1 function compromises assembly and proton-pumping activity of the vacuolar-ATPase on lysosomes, leading to defective lysosomal acidification and marked impairment of autophagy. Additional dysregulation of cellular Ca2+ by mutant PS1 in FAD has been ascribed to altered ion channels in the endoplasmic reticulum; however, rich stores of Ca2+ in lysosomes are also abnormally released in PS1-deficient cells secondary to the lysosomal acidification defect. The resultant rise in cytosolic Ca2+ activates Ca2+-dependent enzymes, contributing substantially to calpain overactivation that is a final common pathway leading to neurofibrillary degeneration in all forms of AD (Alzheimer's disease). In the present review, we discuss the close inter-relationships among deficits of lysosomal function, autophagy and Ca2+ homoeostasis as a pathogenic process in PS1-related FAD and their relevance to sporadic AD.