Ionic and signal transduction alterations in Alzheimer’s disease

Several lines of, evidence indicate that Alzheimer’s disease (AD) has systemic expression. Systemic changes are manifested as alterations in a number of molecular and cellular processes. Although, these alterations appear to have little or no consequence in peripheral systems, their parallel expression in the central nervous system (CNS) could account for the principal clinical manifestations of the disease. Recent research seems to indicate that alterations in ion channels, calcium homeostasis, and protein kinase C (PKC) can be linked and thereby constitute a model of pathophysiological relevance. Considering the difficulties of studying dynamic pathophysiological processes in the disease-ridden postmortem AD brain, peripheral tissues such as fibroblasts provide a suitable model to study molecular and cellular aspects of the disease.     

Alzheimer’s disease related genes during primate evolution

During primate evolution, the neuronal and cognition-related genes have evolved rapidly. These genes seem to induce neurological illnesses such as Alzheimer’s disease (AD). In this study, we analyzed genes APOE, TOMM40, and PICALM known as the risk factors of AD. We performed bioinformatics analyses in relation to evolution, phylogeny, and protein structure for those genes in humans, Neanderthals, chimpanzees, bonobos, gorillas, orangutans, crab-eating monkeys, and rhesus monkeys. Cholesterol-related genes showed relatively rapid evolution toward a lower risk of AD. Neanderthals showed relatively higher polymorphism in genes APOE, TOMM40, and PICALM than humans did. Phylogeny indicated different topologies in the trichotomy of humans, chimpanzees, and gorillas in terms of genes APOE, TOMM40, and PICALM. These results provide to hominin-specific patterns in three genes, and give clues to the modern human-specific traits of AD and shed light on further functional research helping to understand AD.     

New approaches for the treatment of Alzheimer’s disease

Alzheimer’s disease (AD) is the most prevalent chronic neurodegenerative disease. Current approved therapies are symptomatic treatments having some effect on cognitive function. Therapies that target β-amyloid (Aβ) have been the focus of efforts to develop a disease modification treatment for AD but these approaches have failed to show any clinical benefit so far. Beyond the ‘Aβ hypothesis’, there are a number of newer approaches to treat AD with neuroinflammation emerging as a very active area of research based on risk gene analysis. This short review will summarize approved drug therapies, recent clinical trials and new approaches for the treatment of AD.     

Homeostasis of metals in the progression of Alzheimer’s disease

In order to study the involvement of metals in the progression of Alzheimer’s disease, serum samples from patients with Alzheimer and mild cognitive impairment were investigated. For this purpose, metal content was analyzed after size-fractionation of species and then, inter-element and inter-fraction ratios were computed. In this way, the analysis allowed discovering changes that could be used as markers of disease, but also provided a new insight into the interactions in the homeostasis of elements in neurodegeneration and its progression. Aluminum and labile forms of iron and copper were increased in demented patients, while manganese, zinc and selenium were reduced. Interestingly, levels of different elements, principally iron, aluminum and manganese, were closely inter-related, which could evidence a complex interdependency between the homeostasis of the different metals in this disorder. On the other hand, imbalances in metabolism of copper, zinc and selenium could be associated to abnormal redox status. Therefore, this study may contribute to our understanding of the pathological mechanisms related to metals in Alzheimer’s disease.     

Role of purinergic receptors in the Alzheimer’s disease

Etiology of the Alzheimer’s disease (AD) is not fully understood. Different pathological processes are considered, such as amyloid deposition, tau protein phosphorylation, oxidative stress (OS), metal ion disregulation, or chronic neuroinflammation. Purinergic signaling is involved in all these processes, suggesting the importance of nucleotide receptors (P2X and P2Y) and adenosine receptors (A1, A2A, A2B, A3) present on the CNS cells. Ecto-purines, ecto-pyrimidines, and enzymes participating in their metabolism are present in the inter-cellular spaces. Accumulation of amyloid-β (Aβ) in brain induces the ATP release into the extra-cellular space, which in turn stimulates the P2X7 receptors. Activation of P2X7 results in the increased synthesis and release of many pro-inflammatory mediators such as cytokines and chemokines. Furthermore, activation of P2X7 leads to the decreased activity of α-secretase, while activation of P2Y2 receptor has an opposite effect. Simultaneous inhibition of P2X7 and stimulation of P2Y2 would therefore be the efficient way of the α-secretase activation. Activation of P2Y2 receptors present in neurons, glia cells, and endothelial cells may have a positive neuroprotective effect in AD. The OS may also be counteracted via the purinergic signaling. ADP and its non-hydrolysable analogs activate P2Y13 receptors, leading to the increased activity of heme oxygenase, which has a cytoprotective activity. Adenosine, via A1 and A2A receptors, affects the dopaminergic and glutaminergic signaling, the brain-derived neurotrophic factor (BNDF), and also changes the synaptic plasticity (e.g., causing a prolonged excitation or inhibition) in brain regions responsible for learning and memory. Such activity may be advantageous in the Alzheimer’s disease.     

Evolution of Alzheimer’s disease pathogenesis conception

Alzheimer’s disease (AD) is a neurodegenerative disorder that becomes a cause of dementia during atrophic brain changes. There are two distinguished forms of AD: familial early-onset form (FAD, approximately 5% of all cases, develops before age 65, most commonly 40–50) and sporadic late-onset form (SAD, approximately 95% of all cases, develops after 65). Identification of genetic determinants of FAD development and evidence of amyloid-beta peptide’s (Aβ) neurotoxicity as a central event in the cascade of pathological processes significantly expanded the conception of molecular and genetic mechanisms of the disease. However, the question of whether or not the accumulation of Aβ is the triggering factor of more widespread SAD remains open. There are a growing number of arguments for Aβ overproduction being the secondary, concomitant event of AD pathological processes: synaptic failure, hyperphosphorylation of tau protein, neuroinflammation, neuronal loss, and cognitive decline. As one of triggering risk factors of AD development, mitochondrial dysfunction is considered, with the decrease in ATP synthesis and oxidative stress becoming the consequences. However, the specific molecular and genetic mechanisms of AD remain unclear. This is caused by the lack of relevant animal models for studying mechanisms of the disease and objective estimation of pathogenically justified methods of AD prevention and treatment.     

The study of Alzheimer’s disease biomarkers

Alzheimer’s disease (AD) is by far the most common dementing illness of late life and is increasing with the ever-growing number of older adults, in particular, in developed countries. The disease is often referred to as the “Long-Goodbye” because the person with the illness slowly becomes lost to everyone a long time before the body finally gives out. Being able to detect AD earlier on during the course of the disease offers better prospects for the future, for AD individuals, their families and friends as well as on the economy, as a whole. Unfortunately, such a detection technique is not yet, available. However, there are a number of promising biological markers (biomarkers) that correlate well with clinical cognitive tests of individuals and/or postmortem histopathological manifestations of the disease, especially when at least two markers are used for the diagnosis. Biosensors are tools that combine a biochemical binding element to a signal conversion unit and are already being used in the study of some AD biomarkers. However, their use in clinical diagnosis remains a challenge. Introduction of nanotechnology leading to nanobiosensors has several potential advantages over other clinical and/or existing analytical tools, including increased assay speed, flexibility, reduced cost of diagnostic testing, potential to deliver molecular diagnostic tools to family general practitioners, and other health care systems. Even more important, nano-based assays have the potential to detect target proteins at attomolar concentration level. They are, therefore, being increasingly exploited for the detection of early metabolic changes associated with diseases. Because brain damage is irreversible, the use of nanotechnology is particularly important in AD and other neurodegenerative disorders. Nanosensors can also facilitate and enable pointofcare-testing (POCT). This article reviews the basic biochemical processes that lead to AD pathology, current biomarkers for AD, and the current role of nanosensor technology for the study of AD biomarkers. Furthermore, it discusses the huge potential of nanosensing to deliver new molecular diagnostic strategies to AD research.     

Copper in the brain and Alzheimer’s disease

Alzheimer’s disease (AD) is the most common form of neurodegenerative disease. The brain is particularly vulnerable to oxidative damage induced by unregulated redox-active metals such as copper and iron, and the brains of AD patients display evidence of metal dyshomeostasis and increased oxidative stress. The colocalisation of copper and amyloid β (Aβ) in the glutamatergic synapse during NMDA-receptor-mediated neurotransmission provides a microenvironment favouring the abnormal interaction of redox-potent Aβ with copper under conditions of copper dysregulation thought to prevail in the AD brain, resulting in the formation of neurotoxic soluble Aβ oligomers. Interactions between Aβ oligomers and copper can further promote the aggregation of Aβ, which is the core component of extracellular amyloid plaques, a central pathological hallmark of AD. Copper dysregulation is also implicated in the hyperphosphorylation and aggregation of tau, the main component of neurofibrillary tangles, which is also a defining pathological hallmark of AD. Therefore, tight regulation of neuronal copper homeostasis is essential to the integrity of normal brain functions. Therapeutic strategies targeting interactions between Aβ, tau and metals to restore copper and metal homeostasis are discussed.     

The next step of neurogenesis in the context of Alzheimer’s disease

Molecular Biology Reports - Among different pathological mechanisms, neuronal loss and neurogenesis impairment in the hippocampus play important roles in cognitive decline in Alzheimer’s...     

Features of ceruloplasmin in the cerebrospinal fluid of Alzheimer’s disease patients

The level of the apo-form of the copper enzyme ceruloplasmin (CP) is an established peripheral marker in diseases associated with copper imbalance. In view of the proposal that disturbances of copper homeostasis may contribute to neurodegeneration associated with Alzheimer’s disease (AD), the present work investigates, by Western blot and non-reducing SDS-PAGE followed by activity staining, the features of CP protein, and the copper/CP relationship in cerebrospinal fluid (CSF) and serum of AD patients. Results show that only a fraction of total copper is associated with CP in the CSF, at variance with serum, both in affected and in healthy individuals. Furthermore, a conspicuous amount of apo-ceruloplasmin and a decrease of CP oxidase activity characterize the CSF of the affected individuals, and confirm that an impairment of copper metabolism occurs in their central nervous system. In the CSF of AD patients the decrease of active CP, associated with the increase in the pool of copper not sequestered by this protein, may play a role in the neurodegenerative process.     

Pushing the boundaries of brain organoids to study Alzheimer’s disease

Progression of Alzheimer’s disease (AD) entails deterioration or aberrant function of multiple brain cell types, eventually leading to neurodegeneration and cognitive decline. Defining how complex cell–cell interactions become dysregulated in AD requires novel human cell-based in vitro platforms that could recapitulate the intricate cytoarchitecture and cell diversity of the human brain. Brain organoids (BOs) are 3D self-organizing tissues that partially resemble the human brain architecture and can recapitulate AD-relevant pathology. In this review, we highlight the versatile applications of different types of BOs to model AD pathogenesis, including amyloid-β and tau aggregation, neuroinflammation, myelin breakdown, vascular dysfunction, and other phenotypes, as well as to accelerate therapeutic development for AD.     

Biomarkers of Alzheimer’s disease in body fluids

Various innovative diagnostic methods for Alzheimer’s disease (AD) have been developed in view of the increasing preva-lence and consequences of later-life dementia. Biomarkers in cerebrospinal fluid (CSF) and blood for AD are primarily based on the detection of components derived from amyloid plaques and neurofibrillary tangles (NFTs). Published reports on CSF and blood biomarkers in AD indicate that although biomarkers in body fluids may be utilized in the clinical diagnosis of AD, there are no specific markers that permit accurate and reliable diagnosis of early-stage AD or the monitoring of disease pro-gression.     

GPCR,a rider of Alzheimer’s disease

Alzheimer’s disease (AD) is the most common type of dementia that affects thinking, learning, memory and behavior of older people. Based on the previous studies, three pathogenic pathways are now commonly accepted as the culprits of this disease namely, amyloid-β pathway, tauopathology and cholinergic dysfunction. This review focuses on the current findings on the regulatory roles of G protein-coupled receptors (GPCRs) in the pathological progression of AD and discusses the potential of the GPCRs as novel therapeutic targets for AD.     

A standard model of Alzheimer’s disease?

ABSTRACT

The recent Research Framework proposed by the US National Institute on Aging and the Alzheimer’s Association (NIA-AA) recommends that Alzheimer’s disease be defined by its specific biology rather than by non-specific neurodegenerative and syndromal features. By affirming markers of abnormal Aβ and tau proteins as the essential pathobiological signature of Alzheimer’s disease, the Framework tacitly reinforces the amyloid (Aβ) cascade as the leading theory of Alzheimer pathogenesis. In light of recent evidence that the cascade is driven by the misfolding and templated aggregation of Aβ and tau, we believe that an empirically grounded Standard Model of Alzheimer’s pathogenesis is within reach. A Standard Model can clarify and consolidate existing information, contextualize risk factors and the complex disease phenotype, identify testable hypotheses for future research, and pave the most direct path to effective prevention and treatment.