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.     

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.     

Amyloid-β as a biomarker for Alzheimer’s disease: quantification methods in body fluids

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, characterized by neuronal impairment leading to dramatic changes in brain. Amyloid-β peptides and tau protein are the most promising biomarkers for AD. Cerebrospinal fluid and plasma are used to determine the concentration of these species. Since the pathological processes of AD start decades before the first symptoms, biomarkers may provide the possibility of early disease detection. The application of rapidly emerging technology, such as mass spectrometry, has opened new avenues to accelerate biomarker discovery, both for diagnostic as well as for prognostic purposes. This review summarizes AD biomarker studies with focus on amyloid-β peptides in biological fluids and their quantification with immunoassays as well as the latest mass spectrometry-based methods.     

Chasing genes in Alzheimer’s and Parkinson’s disease

Alzheimers disease (AD), the most common type of dementia, and Parkinsons disease (PD), the most common movement disorder, are both neurodegenerative adult-onset diseases characterized by the progressive loss of specific neuronal populations and the accumulation of intraneuronal inclusions. The search for genetic and environmental factors that determine the fate of neurons during the ageing process has been a widespread approach in the battle against neurodegenerative disorders. Genetic studies of AD and PD initially focused on the search for genes involved in the aetiological mechanisms of monogenic forms of these diseases. They later expanded to study hundreds of patients, affected relative-pairs and population-based studies, sometimes performed on special isolated populations. A growing number of genes (and pathogenic mutations) is being identified that cause or increase susceptibility to AD and PD. This review discusses the way in which strategies of gene hunting have evolved during the last few years and the significance of finding genes such as the presenilins, -synuclein, parkin and DJ-1. In addition, we discuss possible links between these two neurodegenerative disorders. The clinical, pathological and genetic presentation of AD and PD suggests the involvement of a few overlapping interrelated pathways. Their imbricate features point to a spectrum of neurodegeneration (tauopathies, synucleinopathies, amyloidopathies) that need further intense investigation to find the missing links.     

Alterations in lipid,amino acid,and energy metabolism distinguish Crohn’s disease from ulcerative colitis and control subjects by serum metabolomic profiling

Introduction

Biomarkers are needed in inflammatory bowel disease (IBD) to help define disease activity and identify underlying pathogenic mechanisms. We hypothesized that serum metabolomics, which produces unique metabolite profiles, can aid in this search.

Objectives

The aim of this study was to characterize serum metabolomic profiles in patients with IBD, and to assess for differences between patients with ulcerative colitis (UC), Crohn’s disease (CD), and non-IBD subjects.

Methods

Serum samples from 20 UC, 20 CD, and 20 non-IBD control subjects were obtained along with patient characteristics, including medication use and clinical disease activity. Non-targeted metabolomic profiling was performed using ultra-high performance liquid chromatography/mass spectrometry (UPLC-MS/MS) optimized for basic or acidic species and hydrophilic interaction liquid chromatography (HILIC/UPLC-MS/MS).

Results

In total, 671 metabolites were identified. Comparing IBD and control subjects revealed 173 significantly altered metabolites (27 increased and 146 decreased). The majority of the alterations occurred in lipid-, amino acid-, and energy-related metabolites. Comparing only CD and control subjects revealed 286 significantly altered metabolites (54 increased and 232 decreased), whereas comparing UC and control subjects revealed only five significantly altered metabolites (all decreased). Hierarchal clustering using significant metabolites separated CD from UC and control subjects.

Conclusions

We demonstrate that a number of lipid-, amino acid-, and tricarboxylic acid cycle-related metabolites were significantly altered in IBD patients, more specifically in CD. Therefore, alterations in lipid and amino acid metabolism and energy homeostasis may play a key role in the pathogenesis of CD.

     

Age-related changes in saccadic eye movements in healthy subjects and patients with Parkinson’s disease

The age-related changes in saccadic eye movements (the latency, the duration of single saccades and the percentage of multistep saccades) were compared in healthy subjects and patients with Parkinson’s disease. Healthy volunteers without neurological symptoms were divided into six age groups: (17–20, 21–30, 31–40, 41–50, 51–60, and 61–75 years of age); and parkinsonian patients, into three groups (41–50, 51–60, and 61–75 years of age). According to the data obtained, the saccade characteristics depend on the age in both the subjects without neurological symptoms and parkinsonian patients. In healthy volunteers, the percentage of multistep saccades and the mean saccade latency increase significantly after the age of 60 years. These parameters in patients with Parkinson’s disease significantly exceed the values in healthy subjects from the age-matched groups. The “disease” factor has a greater influence on the saccade latency and the percentage of multistep saccades than the “age” factor. The duration of single saccades depends on age to a lesser degree and does not change in patients with Parkinson’s disease. The peculiarities of the development of neurodegenerative processes in cases of normal aging and in idiopathic parkinsonism are discussed.     

Metabolomics and mitochondrial dysfunction in Alzheimer’s disease

Alzheimer’s disease (AD) is characterized by cognitive impairment, progressive neurodegeneration, and Aβ accumulation. Aβ oligomers can lead to synaptic damage via alterations in glutamate receptors and excitotoxicity, as well as mitochondrial dysfunction. AD is associated with various biological indicators, including (1) predisposing factors such as genetic risk factors, (2) laboratory markers such as Aβ and tau protein, and (3) diagnostic markers such as MRI and PET findings. However, these markers are not confirmed, invasive, or expensive. In the present study, we employed nuclear magnetic resonance (NMR) methods that are inexpensive, time-efficient, and can be performed using samples obtained from various easily accessible sources such as cerebrospinal fluid, plasma, and peripheral tissue, thus highlighting the clinical utility of this approach. NMR analyses of blood metabolites showed that glutamine, glutamate, leucine, oxaloacetate, aspartate, isoleucine, and 3-hydroxyisovalerate are increased in patients with AD compared with control individuals. These metabolites seem to be related to mitochondrial dysfunction. Our data indicated that 3-hydroxyisovalerate, which is linked to known pathologic processes associated with mitochondrial dysfunction and accelerated neurodegeneration, was increased in the blood samples of patients with AD.     

Alzheimer’s disease and gut microbiota

Alzheimer’s disease (AD) is a most common neurodegenerative disorder, which associates with impaired cognition. Gut microbiota can modulate host brain function and behavior via microbiota-gut-brain axis, including cognitive behavior. Germ-free animals, antibiotics, probiotics intervention and diet can induce alterations of gut microbiota and gut physiology and also host cognitive behavior, increasing or decreasing risks of AD. The increased permeability of intestine and blood-brain barrier induced by gut microbiota disturbance will increase the incidence of neurodegeneration disorders. Gut microbial metabolites and their effects on host neurochemical changes may increase or decrease the risk of AD. Pathogenic microbes infection will also increase the risk of AD, and meanwhile, the onset of AD support the “hygiene hypothesis”. All the results suggest that AD may begin in the gut, and is closely related to the imbalance of gut microbiota. Modulation of gut microbiota through personalized diet or beneficial microbiota intervention will probably become a new treatment for AD.     

TREM2 in Alzheimer’s disease

Recent works have demonstrated a rare functional variant (R47H) in triggering receptor expressed on myeloid cells (TREM) 2 gene, encoding TREM2 protein, increase susceptibility to late-onset Alzheimer’s disease (AD), with an odds ratio similar to that of the apolipoprotein E ε4 allele. The reduced function of TREM2 was speculated to be the main cause in the pathogenic effects of this risk variant, and TREM2 is highly expressed in white matter, as well as in the hippocampus and neocortex, which is partly consistent with the pathological features reported in AD brain, indicating the possible involvement of TREM2 in AD pathogenesis. Emerging evidence has demonstrated that TREM2 could suppress inflammatory response by repression of microglia-mediated cytokine production and secretion, which may prevent inflammation-induced bystander damage of neurons. TREM2 also participates in the regulation of phagocytic pathways that are responsible for the removal of neuronal debris. In this article, we review the recent epidemiological findings of TREM2 that related with late-onset AD and speculate the possible roles of TREM2 in progression of this disease. Based on the potential protective actions of TREM2 in AD pathogenesis, targeting TREM2 might provide new opportunities for AD treatment.     

Copper transport and Alzheimer’s disease

This brief review discusses copper transport in humans, with an emphasis on knowledge learned from one of the simplest model organisms, yeast. There is a further focus on copper transport in Alzheimer’s Disease (AD). Copper homeostasis is essential for the well-being of all organisms, from bacteria to yeast to humans: survival depends on maintaining the required supply of copper for the many enzymes, dependent on copper for activity, while ensuring that there is no excess free copper, which would cause toxicity. A virtual orchestra of proteins are required to achieve copper homeostasis. For copper uptake, Cu(II) is first reduced to Cu(I) via a membrane-bound reductase. The reduced copper can then be internalised by a copper transporter where it is transferred to copper chaperones for transport and specific delivery to various organelles. Of significance are internal copper transporters, ATP7A and ATP7B, notable for their role in disorders of copper deficiency and toxicity, Menkes and Wilson’s disease, respectively. Metallothioneins and Cu/Zn superoxide dismutase can protect against excess copper in cells. It is clear too, increasing age, environmental and lifestyle factors impact on brain copper. Studies on AD suggest an important role for copper in the brain, with some AD therapies focusing on mobilising copper in AD brains. The transport of copper into the brain is complex and involves numerous players, including amyloid precursor protein, Aβ peptide and cholesterol.     

Blood–brain-barriers in aging and in Alzheimer’s disease

The aging process correlates with a progressive failure in the normal cellular and organ functioning; these alterations are aggravated in Alzheimer’s disease (AD). In both aging and AD there is a general decrease in the capacity of the body to eliminate toxic compounds and, simultaneously, to supply the brain with relevant growth and nutritional factors. The barriers of the brain are targets of this age related dysfunction; both the endothelial cells of the blood–brain barrier and the choroid plexus epithelial cells of the blood-cerebrospinal fluid barrier decrease their secretory capacity towards the brain and their ability to remove toxic compounds from the brain. Additionally, during normal aging and in AD, the permeability of the brain barriers increase. As such, a greater contact of the brain parenchyma with the blood content alters the highly controlled neural environment, which impacts on neural function. Of interest, the brain barriers are more than mere obstacles to the passage of molecules and cells, and therefore active players in brain homeostasis, which is still to be further recognized and investigated in the context of health and disease. Herein, we provide a review on how the brain barriers change during aging and in AD and how these processes impact on brain function.     

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.     

Genetic discoveries and advances in late-onset Alzheimer’s disease

Alzheimer’s disease (AD) is a heterogeneous disorder with multiple patterns of clinical manifestations. Recently, due to the advance of linkage studies, next-generation sequencing and genome-wide association studies, a large number of putative risk genes for AD have been identified using acquired genome mega data. The genetic association between three causal genes, including amyloid precursor protein, presenilin1, and presenilin2 in early-onset AD (EOAD), was discovered over the past few decades. These discoveries showed that there should be additional genetic risk factors for both EOAD and late-onset AD (LOAD) to help fully explain the leading molecular mechanisms in a single pathophysiological entity. This study reviews the clinical features and genetic etiology of LOAD and discusses a variety of AD-mediated genes that are involved in cholesterol and lipid metabolism, endocytosis, and immune response according to their mutations for more efficient selection of functional candidate genes for LOAD. New mechanisms and pathways have been identified as a result.     

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.     

Peripheral immune system in aging and Alzheimer’s disease

Alzheimer’s disease (AD) represents an urgent public health mandate. AD is no longer considered a neural-centric disease; rather, a plethora of recent studies strongly implicate a critical role played by neuroinflammation in the pathogeneses of AD and other neurodegenerative conditions. A close functional connection between the immune system and central nervous system is increasingly recognized. In late-onset AD, aging represents the most significant risk factor. Here, from an immunological perspective, we summarize the prominent molecular and cellular changes in the periphery of aging individuals and AD patients. Moreover, we review the knowledge gained in the past several years that implicate specific arms of the peripheral immune system and other types of immune responses in modulating AD progression. Taken together, these findings collectively emphasize a dynamic role of a concert of brain-extrinsic, peripheral signals in the aging and degenerative processes in the CNS. We believe that a systematic view synthesizing the vast amounts of existing results will help guide the development of next-generation therapeutics and inform future directions of AD investigation.