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Intracellular tau fibrils are sources of neurotoxicity and oxidative stress in Alzheimer's. Current drug discovery efforts have focused on molecules with tau fibril disaggregation and antioxidation functions. However, recent studies suggest that membrane-bound tau-containing oligomers (mTCOs), smaller and less ordered than tau fibrils, are neurotoxic in the early stage of Alzheimer's. Whether tau fibril-targeting molecules are effective against mTCOs is unknown. The binding of epigallocatechin-3-gallate (EGCG), CNS-11, and BHT-CNS-11 to in silico mTCOs and experimental tau fibrils was investigated using machine learning-enhanced docking and molecular dynamics simulations. EGCG and CNS-11 have tau fibril disaggregation functions, while the proposed BHT-CNS-11 has potential tau fibril disaggregation and antioxidation functions like EGCG. Our results suggest that the three molecules studied may also bind to mTCOs. The predicted binding probability of EGCG to mTCOs increases with the protein aggregate size. In contrast, the predicted probability of CNS-11 and BHT-CNS-11 binding to the dimeric mTCOs is higher than binding to the tetrameric mTCOs for the homo tau but not for the hetero tau–amylin oligomers. Our results also support the idea that anionic lipids may promote the binding of molecules to mTCOs. We conclude that tau fibril-disaggregating and antioxidating molecules may bind to mTCOs, and that mTCOs may also be useful targets for Alzheimer's drug design. [ABSTRACT FROM AUTHOR]

The quantification of neurofibrillary tangles (NFTs) using specific PET tracers can facilitate the diagnosis of Alzheimer's disease (AD) and allow monitoring of disease progression and treatment efficacy. [18F]-THK523 has shown high affinity and selectivity for tau pathology. However, its high retention in white matter, which makes simple visual inspection difficult, may limit its use in research or clinical settings. In this paper, we optimized the automated radiosynthesis of [11C]-TKF and evaluated its biodistribution and toxicity in C57 mice. [11C]-TKF can be made by reaction precursor with [11C]MeOTf or 11CH3I, but [11C]MeOTf will give us higher labeling yields and specific activity. [11C]-TKF presented better brain uptake in normal mouse than [18F]-THK523 (3.23% ± 1.25% ID.g-1 vs. 2.62% ± 0.39% ID.g-1 at 2 min post-injection). The acute toxicity studies of [11C]-TKF were unremarkable. [ABSTRACT FROM AUTHOR]

Human Tau protein is the most reliable biomarker for the prediction of Alzheimer's disease (AD). However, the assay to detect low concentrations of tau protein in serum is a great challenge for the early diagnosis of AD. This paper reports an electrochemiluminescence (ECL) immunosensor for Tau protein in serum samples. Gold nanostars (AuNSs) decorated on carbon nitride nanosheets (AuNS@g-CN nanostructure) show highly strong and stable ECL activity compared to pristine CN nanosheets due to the electrocatalytic and surface plasmon effects of AuNSs. As a result of the strong electromagnetic field at branches, AuNSs showed a better ECL enhancement effect than their spherical counterpart. For the fabrication of a specific immunosensor, immobilized AuNSs were functionalized with a monoclonal antibody specific for Tau protein. In the presence of Tau protein, the ECL intensity of the immunosensor decreased considerably. Under the optimal conditions, this ECL based immunosensor exhibits a dynamic linear range from 0.1 to 100 ng mL−1 with a low limit of detection of 0.034 ng mL−1. The LOD is less than the Tau level in human serum; thus, this study provides a useful method for the determination of Tau. The fabricated ECL immunosensor was successfully applied to the detection of Tau, the biomarker in serum samples. Therefore, the present approach is very promising for application in diagnosing AD within the early stages of the disease. [ABSTRACT FROM AUTHOR]

Neurodegeneration of the brain after ischemia is a major cause of severe, long-term disability, dementia, and mortality, which is a global problem. These phenomena are attributed to excitotoxicity, changes in the blood–brain barrier, neuroinflammation, oxidative stress, vasoconstriction, cerebral amyloid angiopathy, amyloid plaques, neurofibrillary tangles, and ultimately neuronal death. In addition, genetic factors such as post-ischemic changes in genetic programming in the expression of amyloid protein precursor, β-secretase, presenilin-1 and -2, and tau protein play an important role in the irreversible progression of post-ischemic neurodegeneration. Since current treatment is aimed at preventing symptoms such as dementia and disability, the search for causative therapy that would be helpful in preventing and treating post-ischemic neurodegeneration of Alzheimer's disease proteinopathy is ongoing. Numerous studies have shown that the high contents of flavonoids and phenolic acids in honey have antioxidant, anti-inflammatory, anti-apoptotic, anti-amyloid, anti-tau protein, anticholinesterase, serotonergic, and AMPAK activities, influencing signal transmission and neuroprotective effects. Notably, in many preclinical studies, flavonoids and phenolic acids, the main components of honey, were also effective when administered after ischemia, suggesting their possible use in promoting recovery in stroke patients. This review provides new insight into honey's potential to prevent brain ischemia as well as to ameliorate damage in advanced post-ischemic brain neurodegeneration. [ABSTRACT FROM AUTHOR]

Intracellular tau accumulation is a hallmark pathology of Alzheimer's disease (AD) and other tauopathies. Tau protein, in the hyperphosphorylated form, is the component of paired helical filaments (PHFs) and neurofibrillary tangles (NFTs) in AD. Blocking tau aggregation and/or phosphorylation is currently a promising strategy for AD treatment. Here, we elucidate that quercetagitrin, a natural compound derived from African marigold (Tagetes erecta), could inhibit tau aggregation and reduce tau phosphorylation at multiple disease-related sites in vitro. Moreover, the in vivo effect of quercetagitrin was assessed in P301S-tau transgenic via oral administration. The compound treatment restored the cognitive deficits and neuron loss in the mice. The formation of NFTs and tau phosphorylations in the hippocampus and cortex of the mice was also prevented by the compound. Moreover, quercetagitrin feeding displayed neuroinflammation protection through the inhibition of NF-κB activation in the mice. Together, our data reveal that quercetagitrin possesses the potential to further develop as a therapeutic medicine for AD and other tauopathies. [ABSTRACT FROM AUTHOR]

In the last two decades, the amyloid hypothesis, i.e., the abnormal accumulation of toxic Aβ assemblies in the brain, has been considered the mainstream concept sustaining research in Alzheimer's Disease (AD). However, the course of cognitive decline and AD development better correlates with tau accumulation rather than amyloid peptide deposition. Moreover, all clinical trials of amyloid-targeting drug candidates have been unsuccessful, implicitly suggesting that the amyloid hypothesis needs significant amendments. Accumulating evidence supports the existence of a series of potentially dangerous relationships between Aβ oligomeric species and tau protein in AD. However, the molecular determinants underlying pathogenic Aβ/tau cross interactions are not fully understood. Here, we discuss the common features of Aβ and tau molecules, with special emphasis on: (i) the critical role played by metal dyshomeostasis in promoting both Aβ and tau aggregation and oxidative stress, in AD; (ii) the effects of lipid membranes on Aβ and tau (co)-aggregation at the membrane interface; (iii) the potential of small peptide-based inhibitors of Aβ and tau misfolding as therapeutic tools in AD. Although the molecular mechanism underlying the direct Aβ/tau interaction remains largely unknown, the arguments discussed in this review may help reinforcing the current view of a synergistic Aβ/tau molecular crosstalk in AD and stimulate further research to mechanism elucidation and next-generation AD therapeutics. [ABSTRACT FROM AUTHOR]

The amyloid hypothesis of Alzheimer's disease has long been the predominant theory, suggesting that Alzheimer's disease is caused by the accumulation of amyloid beta protein (Aβ) in the brain, leading to neuronal toxicity in the central nervous system (CNS). Because of breakthroughs in molecular medicine, the amyloid pathway is thought to be central to the pathophysiology of Alzheimer's disease (AD). Currently, it is believed that altered biochemistry of the Aβ cycle remains a central biological feature of AD and is a promising target for treatment. This review provides an overview of the process of amyloid formation, explaining the transition from amyloid precursor protein to amyloid beta protein. Moreover, we also reveal the relationship between autophagy, cerebral blood flow, ACHE, expression of LRP1, and amyloidosis. In addition, we discuss the detailed pathogenesis of amyloidosis, including oxidative damage, tau protein, NFTs, and neuronal damage. Finally, we list some ways to treat AD in terms of decreasing the accumulation of Aβ in the brain. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), which is among the most prevalent neurodegenerative diseases, manifests as increasing memory loss and cognitive decline. Tau phosphorylation and aggregation are strongly linked to neurodegeneration, as well as associated with chronic neuroinflammatory processes. The anti-inflammation effects of natural products have led to wide recognition of their potential for use in treating and preventing AD. This study investigated whether eupatin, a polymethoxyflavonoid found in Artemisia species, has inhibitory effects on neuroinflammation and tau phosphorylation. We treated mouse macrophages and microglia cells with lipopolysaccharides (LPSs) to activate inflammatory signals, and we treated neuronal cells with a protein phosphatase 2A inhibitor, okadaic acid (OA), or transfection with pRK5-EGFP-Tau P301L plasmid to induce tau phosphorylation. The results indicated that eupatin significantly reduced the LPS-induced protein expression and phosphorylation of p65 and inducible nitric oxide synthase as well as downstream products interleukin 6 and nitrite, respectively. Furthermore, eupatin markedly inhibited the expression of phospho-tau in response to OA treatment and plasmid transfection. We discovered that this inhibition was achieved through the inhibition of glycogen synthase kinase 3β (GSK3β), and molecular docking results suggested that eupatin can sufficiently bind to the GSK3β active site. Our results demonstrate that eupatin has neuroprotective effects, making it suitable for AD treatment. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common form of dementia and results in progressive neurodegeneration. The incidence rate of AD is increasing, creating a major public health issue. AD is characterized by neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein and senile plaques composed of amyloid-β (Aβ). Currently, a definitive diagnosis of AD is accomplished post-mortem. Thus, the use of molecular probes that are able to selectively bind to NFTs or Aβ can be valuable tools for the accurate and early diagnosis of AD. The aim of this review is to summarize and highlight fluorinated molecular probes that can be used for molecular imaging to detect either NFTs or Aβ. Specifically, fluorinated molecular probes used in conjunction with 19F MRI, PET, and fluorescence imaging will be explored. [ABSTRACT FROM AUTHOR]

The structural polymorphism and the physiological and pathophysiological roles of two important proteins, β-amyloid (Aβ) and tau, that play a key role in Alzheimer's disease (AD) are reviewed. Recent results demonstrate that monomeric Aβ has important physiological functions. Toxic oligomeric Aβ assemblies (AβOs) may play a decisive role in AD pathogenesis. The polymorph fibrillar Aβ (fAβ) form has a very ordered cross-β structure and is assumed to be non-toxic. Tau monomers also have several important physiological actions; however, their oligomerization leads to toxic oligomers (TauOs). Further polymerization results in probably non-toxic fibrillar structures, among others neurofibrillary tangles (NFTs). Their structure was determined by cryo-electron microscopy at atomic level. Both AβOs and TauOs may initiate neurodegenerative processes, and their interactions and crosstalk determine the pathophysiological changes in AD. TauOs (perhaps also AβO) have prionoid character, and they may be responsible for cell-to-cell spreading of the disease. Both extra- and intracellular AβOs and TauOs (and not the previously hypothesized amyloid plaques and NFTs) may represent the novel targets of AD drug research. [ABSTRACT FROM AUTHOR]

Ironically, population aging which is considered a public health success has been accompanied by a myriad of new health challenges, which include neurodegenerative disorders (NDDs), the incidence of which increases proportionally to age. Among them, Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common, with the misfolding and the aggregation of proteins being common and causal in the pathogenesis of both diseases. AD is characterized by the presence of hyperphosphorylated τ protein (tau), which is the main component of neurofibrillary tangles (NFTs), and senile plaques the main component of which is β-amyloid peptide aggregates (Aβ). The neuropathological hallmark of PD is α-synuclein aggregates (α-syn), which are present as insoluble fibrils, the primary structural component of Lewy body (LB) and neurites (LN). An increasing number of non-invasive PET examinations have been used for AD, to monitor the pathological progress (hallmarks) of disease. Notwithstanding, still the need for the development of novel detection tools for other proteinopathies still remains. This review, although not exhaustively, looks at the timeline of the development of existing tracers used in the imaging of Aβ and important moments that led to the development of these tracers. [ABSTRACT FROM AUTHOR]