Fluorescent rhodanine-3-acetic acids visualize neurofibrillary tangles in Alzheimer’s disease brains

There is a high demand for the development of an imaging agent for neurofibrillary tangles (NFTs) detection in Alzheimer’s diagnosis. In the present study, a series of rhodanine-3-acetic acids was synthesized and evaluated for fluorescence imaging of NFTs in brain tissues of AD patients. Five out of seven probes have shown excellent binding affinity to NFTs over amyloid plaques in the Thiazine red R displacement assay. However, the selectivity in this in vitro assay is not confirmed by the histopathological evaluation, which indicates significant differences in the binding sites in the assays. Probe 6 showed binding affinity (IC₅₀ = 19 nM) to tau aggregates which is the highest among this series. Probes 2, 3, 4 and 5 display IC₅₀ values of lower than 100 nM to tau aggregates to displace Thiazine red R. Evaluation of the cytotoxicity of these five probes with human liver carcinoma cells revealed that these compounds excert negligible cytotoxicity. The in vivo studies with zebrafish embryos confirmed negligible cytotoxicity at 24 and 72 h post fertilization.     

Synthesis and biological evaluation of novel styryl benzimidazole derivatives as probes for imaging of neurofibrillary tangles in Alzheimer’s disease

This paper describes the synthesis and biological evaluation of styrylbenzimidazole (SBIM) derivatives as agents for imaging neurofibrillary tangles (NFT) in patients with Alzheimer’s disease (AD). SBIM derivatives were prepared with 4-iodobenzene-1,2-diamine and substituted cinnamaldehydes. In binding experiments using recombinant tau and Aβ_1–42 aggregates, SBIM-3 showed higher affinity for the tau aggregates than Aβ_1–42 aggregates (ratio of K_d values was 2.73). In in vitro autoradiography and fluorescent staining, [¹²⁵I]SBIM-3 (or SBIM-3) bound NFT in sections of AD brain tissue. In biodistribution experiments using normal mice, all [¹²⁵I]SBIM derivatives showed high initial uptake into (3.20–4.11%ID/g at 2 min after the injection) and rapid clearance from (0.12–0.33%ID/g at 60 min after the injection) the brain. In conclusion, appropriate structural modifications of SBIM derivatives could lead to more useful agents for the in vivo imaging of NFT in AD brains.     

Are Alzheimer neurofibrillary tangles insoluble polymers?

The two methods currently available for the bulk isolation of Alzheimer tangles of paired helical filaments (PHF) are based on a brief treatment of a neuronal-enriched preparation with sodium dodecyl sulfate (SDS) (Method I) and on heating of whole brain homogenate with SDS and beta-mercaptoethanol (Method II). PHF were isolated from the same Alzheimer brain by these two methods, subjected to SDS-polyacrylamide gel electrophoresis and immuno-labelled with monoclonal antibodies to PHF after transferring from the gel to nitrocellulose paper. The PHF isolated by method I revealed the presence of 45 kilodalton to 62 kilodalton PHF polypeptides, whereas the PHF isolated by method II were excluded from the gel. However, PHF isolated by both methods were digested with proteinase-K, though the degradation of PHF of method I was considerably more rapid than that of PHF isolated by method II. These findings should establish that the solubility of PHF might depend on the methods employed for their isolation and that they might not be insoluble polymers of covalently crosslinked polypeptides which accumulate irreversibly in the brain of patients with Alzheimer disease.     

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.     

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.     

Modeling Alzheimer’s disease in transgenic rats

Alzheimer’s disease (AD) is the most common form of dementia. At the diagnostic stage, the AD brain is characterized by the accumulation of extracellular amyloid plaques, intracellular neurofibrillary tangles and neuronal loss. Despite the large variety of therapeutic approaches, this condition remains incurable, since at the time of clinical diagnosis, the brain has already suffered irreversible and extensive damage. In recent years, it has become evident that AD starts decades prior to its clinical presentation. In this regard, transgenic animal models can shed much light on the mechanisms underlying this “pre-clinical” stage, enabling the identification and validation of new therapeutic targets. This paper summarizes the formidable efforts to create models mimicking the various aspects of AD pathology in the rat. Transgenic rat models offer distinctive advantages over mice. Rats are physiologically, genetically and morphologically closer to humans. More importantly, the rat has a well-characterized, rich behavioral display. Consequently, rat models of AD should allow a more sophisticated and accurate assessment of the impact of pathology and novel therapeutics on cognitive outcomes.     

Adenosine receptor signalling in Alzheimer’s disease

Purinergic Signalling - Alzheimer’s disease (AD) is the most common dementia in the elderly and its increasing prevalence presents treatment challenges. Despite a better understanding of the...     

Estrogenic hormones receptors in Alzheimer’s disease

Molecular Biology Reports - Estrogens are hormones that play a critical role during development and growth for the adequate functioning of the reproductive system of women, as well as for...     

Trafficking regulation of proteins in Alzheimer’s disease

The β-amyloid (Aβ) peptide has been postulated to be a key determinant in the pathogenesis of Alzheimer’s disease (AD). Aβ is produced through sequential cleavage of the β-amyloid precursor protein (APP) by β- and γ-secretases. APP and relevant secretases are transmembrane proteins and traffic through the secretory pathway in a highly regulated fashion. Perturbation of their intracellular trafficking may affect dynamic interactions among these proteins, thus altering Aβ generation and accelerating disease pathogenesis. Herein, we review recent progress elucidating the regulation of intracellular trafficking of these essential protein components in AD.     

Compensating for synaptic loss in Alzheimer’s disease

Confirming that synaptic loss is directly related to cognitive deficit in Alzheimer’s disease (AD) has been the focus of many studies. Compensation mechanisms counteract synaptic loss and prevent the catastrophic amnesia induced by synaptic loss via maintaining the activity levels of neural circuits. Here we investigate the interplay between various synaptic degeneration and compensation mechanisms, and abnormal cortical oscillations based on a large-scale network model consisting of 100,000 neurons exhibiting several cortical firing patterns, 8.5 million synapses, short-term plasticity, axonal delays and receptor kinetics. The structure of the model is inspired by the anatomy of the cerebral cortex. The results of the modelling study suggest that cortical oscillations respond differently to compensation mechanisms. Local compensation preserves the baseline activity of theta (5–7 Hz) and alpha (8–12 Hz) oscillations whereas delta (1–4 Hz) and beta (13–30 Hz) oscillations are maintained via global compensation. Applying compensation mechanisms independently shows greater effects than combining both compensation mechanisms in one model and applying them in parallel. Consequently, it can be speculated that enhancing local compensation might recover the neural processes and cognitive functions that are associated with theta and alpha oscillations whereas inducing global compensation might contribute to the repair of neural (cognitive) processes which are associated with delta and beta band activity. Compensation mechanisms may vary across cortical regions and the activation of inappropriate compensation mechanism in a particular region may fail to recover network dynamics and/or induce secondary pathological changes in the network.     

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.     

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.     

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.     

The Na+/Ca2+exchanger in Alzheimer’s disease

As a pivotal player in regulating sodium (Na⁺) and calcium (Ca²⁺) homeostasis and signalling in excitable cells, the Na⁺/Ca²⁺ exchanger (NCX) is involved in many neurodegenerative disorders in which an imbalance of intracellular Ca²⁺ and/or Na⁺ concentrations occurs, including Alzheimer’s disease (AD). Although NCX has been mainly implicated in neuroprotective mechanisms counteracting Ca²⁺ dysregulation, several studies highlighted its role in the neuronal responses to intracellular Na⁺ elevation occurring in several pathophysiological conditions. Since the alteration of Na⁺ and Ca²⁺ homeostasis significantly contributes to synaptic dysfunction and neuronal loss in AD, it is of crucial importance to analyze the contribution of NCX isoforms in the homeostatic responses at neuronal and synaptic levels. Some studies found that an increase of NCX activity in brains of AD patients was correlated with neuronal survival, while other research groups found that protein levels of two NCX subtypes, NCX2 and NCX3, were modulated in parietal cortex of late stage AD brains. In particular, NCX2 positive synaptic terminals were increased in AD cohort while the number of NCX3 positive terminals were reduced. In addition, NCX1, NCX2 and NCX3 isoforms were up-regulated in those synaptic terminals accumulating amyloid-beta (Aβ), the neurotoxic peptide responsible for AD neurodegeneration. More recently, the hyperfunction of a specific NCX subtype, NCX3, has been shown to delay endoplasmic reticulum stress and apoptotic neuronal death in hippocampal neurons exposed to Aβ insult. Despite some issues about the functional role of NCX in synaptic failure and neuronal loss require further studies, these findings highlight the putative neuroprotective role of NCX in AD and open new strategies to develop new druggable targets for AD therapy.     

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.     

Network-wide dysregulation of calcium homeostasis in Alzheimer’s disease

Dysregulation of intracellular Ca²⁺ homeostasis has been proposed as a common proximal cause of neural dysfunction during aging and Alzheimer’s disease (AD). In this context, aberrant Ca²⁺ signaling has been viewed as a neuronal phenomenon mostly related to the dysfunction of intracellular Ca²⁺ stores. However, recent data suggest that, in AD, Ca²⁺ dyshomeostasis is not restricted to neurons but represents a global phenomenon affecting virtually all cells in the brain. AD-related aberrant Ca²⁺ signaling in astrocytes and microglia, which is activated during the disease, probably contributes profoundly to an inflammatory response that, in turn, impacts neuronal Ca²⁺ homeostasis and brain function. Based on recent data obtained in vivo and in vitro, we propose that bidirectional interactions between the inflammatory responses of glial cells and aberrant Ca²⁺ signaling represent a vicious cycle accelerating disease progression.