Harmony of Wnt pathway in Alzheimer's: Navigating the multidimensional progression from preclinical to clinical stages.

The Wnt pathway stands out as a pivotal signal transduction pathway, operating through two distinct modes of signaling: the canonical/ß-catenin pathway and the non-canonical pathway. Among these, the canonical pathway assumes a paramount role in various physiological and pathological processes within the human body. Particularly in the brain, Wnt exhibits involvement in fundamental physiological events including neuronal differentiation/survival, axonogenesis, neural stem cell regulation, synaptic plasticity, and cell cycle modulation. Notably, scientific evidence underscores the critical role of the Wnt pathway in the pathogenesis of Alzheimer's disease (AD), correlating with its involvement in key pathological features such as tau tangles, Amyloid-ß plaques, synaptic dysfunction, oxidative stress, mitochondrial dysfunction, cognitive impairments, and disruption of the blood-brain barrier integrity. This review aims to comprehensively explore the involvement and significance of Wnt signaling in Alzheimer's. Furthermore, it delves into recent advancements in research on Wnt signaling, spanning from preclinical investigations to clinical trials.

[18F]Flotaza for Aß Plaque Diagnostic Imaging: Evaluation in Postmortem Human Alzheimer's Disease Brain Hippocampus and PET/CT Imaging in 5xFAD Transgenic Mice.

The diagnostic value of imaging Aß plaques in Alzheimer's disease (AD) has accelerated the development of fluorine-18 labeled radiotracers with a longer half-life for easier translation to clinical use. We have developed [18F]flotaza, which shows high binding to Aß plaques in postmortem human AD brain slices with low white matter binding. We report the binding of [18F]flotaza in postmortem AD hippocampus compared to cognitively normal (CN) brains and the evaluation of [18F]flotaza in transgenic 5xFAD mice expressing Aß plaques. [18F]Flotaza binding was assessed in well-characterized human postmortem brain tissue sections consisting of HP CA1-subiculum (HP CA1-SUB) regions in AD (n = 28; 13 male and 15 female) and CN subjects (n = 32; 16 male and 16 female). Adjacent slices were immunostained with anti-Aß and analyzed using QuPath. In vitro and in vivo [18F]flotaza PET/CT studies were carried out in 5xFAD mice. Post-mortem human brain slices from all AD subjects were positively IHC stained with anti-Aß. High [18F]flotaza binding was measured in the HP CA1-SUB grey matter (GM) regions compared to white matter (WM) of AD subjects with GM/WM > 100 in some subjects. The majority of CN subjects had no decipherable binding. Male AD exhibited greater WM than AD females (AD WM♂/WM♀ > 5; p < 0.001) but no difference amongst CN WM. In vitro studies in 5xFAD mice brain slices exhibited high binding [18F]flotaza ratios (>50 versus cerebellum) in the cortex, HP, and thalamus. In vivo, PET [18F]flotaza exhibited binding to Aß plaques in 5xFAD mice with SUVR~1.4. [18F]Flotaza is a new Aß plaque PET imaging agent that exhibited high binding to Aß plaques in postmortem human AD. Along with the promising results in 5xFAD mice, the translation of [18F]flotaza to human PET studies may be worthwhile.

Polymeric nanoparticles: A promising strategy for treatment of Alzheimer's disease.

Alzheimer's disease (AD), is characterised by two major hallmarks: the formation of extracellular ß-amyloid (Aß) plaques and the hyperphosphorylation of tau protein, thus leading to the formation of neurofibrillary tangles. These hallmarks cause synaptic loss, neuronal damage, and the development of neuroinflammation and oxidative stress, which promote AD progression. Thus, the goal of treating AD is eliminating these hallmarks, to prevent AD progression and decrease symptoms. However, current available therapies provide symptomatic relief rather than treating the underlying cause of the disease, because the restrictive nature of the blood brain barrier (BBB) impedes the entry of drugs, thereby affecting drug efficacy and bioavailability. Researchers are focusing on developing new therapeutic approaches to bypass the BBB, for achieving site-specific drug delivery with the highest possible bioavailability and the lowest adverse effects. Recently explored therapeutic strategies include use of biologic agents such as monoclonal antibodies. Aducanumab, a strong candidate for treating AD, has been granted accelerated Food and Drug Administration approval; however, safety concerns may hinder its future use. Thus, nanotechnological approaches have led to a new era of AD treatment. Nanoparticles (NPs), because of their small particle size, can cross the BBB, thus enhancing drug pharmacokinetic properties and enabling targeted drug delivery. Polymeric NPs have been extensively studied, because of their simple production, biodegradability, biocompatibility, and unique architecture. These NPs provide a flexible vesicle that can be easily tailored to achieve desired physicochemical features. In this review, various types of polymer-based-NPs are discussed, highlighting the properties of fabricated NPs, which have multiple benefits in AD treatment, including anti-amyloid, antioxidant, and anti-inflammatory effects.

Histological and Memory Alterations in an Innovative Alzheimer's Disease Animal Model by Vanadium Pentoxide Inhalation.

Background: Previous work from our group has shown that chronic exposure to Vanadium pentoxide (V2O5) causes cytoskeletal alterations suggesting that V2O5 can interact with cytoskeletal proteins through polymerization and tyrosine phosphatases inhibition, causing Alzheimer's disease (AD)-like hippocampal cell death. Objective: This work aims to characterize an innovative AD experimental model through chronic V2O5 inhalation, analyzing the spatial memory alterations and the presence of neurofibrillary tangles (NFTs), amyloid-ß (Aß) senile plaques, cerebral amyloid angiopathy, and dendritic spine loss in AD-related brain structures. Methods: 20 male Wistar rats were divided into control (deionized water) and experimental (0.02 M V2O5 1 h, 3/week for 6 months) groups (n = 10). The T-maze test was used to assess spatial memory once a month. After 6 months, histological alterations of the frontal and entorhinal cortices, CA1, subiculum, and amygdala were analyzed by performing Congo red, Bielschowsky, and Golgi impregnation. Results: Cognitive results in the T-maze showed memory impairment from the third month of V2O5 inhalation. We also noted NFTs, Aß plaque accumulation in the vascular endothelium and pyramidal neurons, dendritic spine, and neuronal loss in all the analyzed structures, CA1 being the most affected. Conclusions: This model characterizes neurodegenerative changes specific to AD. Our model is compatible with Braak AD stage IV, which represents a moment where it is feasible to propose therapies that have a positive impact on stopping neuronal damage.

Mass spectrometry imaging highlights dynamic patterns of lipid co-expression with Aß plaques in mouse and human brains.

Lipids play crucial roles in the susceptibility and brain cellular responses to Alzheimer's disease (AD) and are increasingly considered potential soluble biomarkers in cerebrospinal fluid (CSF) and plasma. To delineate the pathological correlations of distinct lipid species, we conducted a comprehensive characterization of both spatially localized and global differences in brain lipid composition in AppNL-G-F mice with spatial and bulk mass spectrometry lipidomic profiling, using human amyloid-expressing (h-Aß) and WT mouse brains controls. We observed age-dependent increases in lysophospholipids, bis(monoacylglycerol) phosphates, and phosphatidylglycerols around Aß plaques in AppNL-G-F mice. Immunohistology-based co-localization identified associations between focal pro-inflammatory lipids, glial activation, and autophagic flux disruption. Likewise, in human donors with varying Braak stages, similar studies of cortical sections revealed co-expression of lysophospholipids and ceramides around Aß plaques in AD (Braak stage V/VI) but not in earlier Braak stage controls. Our findings in mice provide evidence of temporally and spatially heterogeneous differences in lipid composition as local and global Aß-related pathologies evolve. Observing similar lipidomic changes associated with pathological Aß plaques in human AD tissue provides a foundation for understanding differences in CSF lipids with reported clinical stage or disease severity.

Mesenchymal Stem Cells Applications in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder that advances gradually and primarily impacts the hippocampus region of the brain. It is defined by a deterioration in cognitive function as well as an observable loss of memory retention. One of the major characteristics of AD is the impairment of neural generation, resulting in the depletion of neurons and synaptic connections within the nervous system. It is unfortunate to say that, at present, no definitive cure is available for AD, and no medication is effective in halting the progression of neurodegeneration associated with it. Nevertheless, it is crucial to highlight that progress has been achieved in addressing the troubling symptoms of AD. The Food and Drug Administration has granted approval for two categories of medications designed to alleviate these symptoms. The scientific community has been inspired by these advancements to investigate alternative therapeutic options, with an emphasis on stem cell therapy in particular. The main focus of this review will be on the potential for the use of a variety of mesenchymal stem cells as a treatment for AD.

Two-Photon Fluorescent Probes for Amyloid-ß Plaques Imaging In Vivo.

Amyloid-ß (Aß) peptide deposition, hyperphosphorylated tau proteins, reactive astrocytes, high levels of metal ions, and upregulated monoamine oxidases are considered to be the primary pathological markers of Alzheimer's disease (AD). Among them, Aß peptide deposition or Aß plaques, is regarded as the initial factor in the pathogenesis of AD and a critical pathological hallmark in AD. This review highlights recently Aß-specific fluorescent probes for two-photon imaging of Aß plaques in vivo. It includes the synthesis and detection mechanism of probes, as well as their application to two-photon imaging of Aß plaques in vivo.

Design and development of benzyl piperazine linked 5-phenyl-1,2,4-triazole-3-thione conjugates as potential agents to combat Alzheimer's disease.

Our present work demonstrates the molecular hybridization-assisted design, synthesis, and biological evaluation of 22 benzylpiperazine-linked 1,2,4-triazole compounds (PD1-22) as AD modifying agents. All the compounds were tested for their in vitro hChEs, hBACE-1, and Aß-aggregation inhibition properties. Among them, compound PD-08 and PD-22 demonstrated good hChE and hBACE-1 inhibition as compared to standards donepezil and rivastigmine. Both compounds displaced PI from PAS at 50 µM concentration which was comparable to donepezil and also demonstrated anti-Aß aggregation properties in self- and AChE-induced thioflavin T assay. Both compounds have shown excellent BBB permeation via PAMPA-BBB assay and were found to be non-neurotoxic at 80 µM concentration against differentiated SH-SY5Y cell lines. Compound PD-22 demonstrated an increase in rescued eye phenotype in Aß-phenotypic drosophila AD model and amelioration of behavioral deficits in the Aß-induced rat model of AD. The in-silico docking studies of compound PD-22 revealed a good binding profile towards CAS and PAS residues of AChE and the catalytic dyad of the BACE-1. The 100 ns molecular dynamics simulation studies of compound PD-22 complexed with AChE and BACE-1 enzymes suggested stable ligand-protein complex throughout the simulation run. Based on our findings compound PD-22 could further be utilized as a lead to design a promising candidate for AD therapy.

Comparison of Monoamine Oxidase-A, Aß Plaques, Tau, and Translocator Protein Levels in Postmortem Human Alzheimer's Disease Brain.

Increased monoamine oxidase-A (MAO-A) activity in Alzheimer's disease (AD) may be detrimental to the point of neurodegeneration. To assess MAO-A activity in AD, we compared four biomarkers, Aß plaques, tau, translocator protein (TSPO), and MAO-A in postmortem AD. Radiotracers were [18F]FAZIN3 for MAO-A, [18F]flotaza and [125I]IBETA for Aß plaques, [124/125I]IPPI for tau, and [18F]FEPPA for TSPO imaging. Brain sections of the anterior cingulate (AC; gray matter GM) and corpus callosum (CC; white matter WM) from cognitively normal control (CN, n = 6) and AD (n = 6) subjects were imaged using autoradiography and immunostaining. Using competition with clorgyline and (R)-deprenyl, the binding of [18F]FAZIN3 was confirmed to be selective to MAO-A levels in the AD brain sections. Increases in MAO-A, Aß plaque, tau, and TSPO activity were found in the AD brains compared to the control brains. The [18F]FAZIN3 ratio in AD GM versus CN GM was 2.80, suggesting a 180% increase in MAO-A activity. Using GM-to-WM ratios of AD versus CN, a >50% increase in MAO-A activity was observed (AD/CN = 1.58). Linear positive correlations of [18F]FAZIN3 with [18F]flotaza, [125I]IBETA, and [125I]IPPI were measured and suggested an increase in MAO-A activity with increases in Aß plaques and tau activity. Our results support the finding that MAO-A activity is elevated in the anterior cingulate cortex in AD and thus may provide a new biomarker for AD in this brain region.

Untangle the mystery behind DS-associated AD - Is APP the main protagonist?

Amyloid precursor protein profusion in Trisomy 21, also called Down Syndrome (DS), is rooted in the genetic determination of Alzheimer's disease (AD). With the recent development in patient care, the life expectancy of DS patients has gradually increased, leading to the high prospect of AD development, consequently leading to the development of plaques of amyloid proteins and neurofibrillary tangles made of tau by the fourth decade of the patient leading to dementia. The altered gene expression resulted in cellular dysfunction due to impairment of autophagy, mitochondrial and lysosomal dysfunction, and copy number variation controlled by the additional genes in Trisomy 21. The cognitive impairment and mechanistic insights underlying DS-AD conditions have been reviewed in this article. Some recent findings regarding biomarkers and therapeutics of DS-AD conditions were highlighted in this review.

GFP-based red-emissive fluorescent probes for dual imaging of ß-amyloid plaques and mitochondrial viscosity.

Alzheimer's disease (AD), with incurable neurodegenerative damage, has attracted growing interest in exploration of better AD biomarkers in its early diagnosis. Among various biomarkers, amyloid-ß (Aß) aggregates and mitochondrial viscosity are closely related to AD and their dual imaging might provide a potential and feasible strategy. In this work, five GFP-based red-emissive fluorescent probes were rationally designed and synthesized for selective detection of ß-amyloid plaques and viscosity, among which C25e exhibited superior properties and could successfully image ß-amyloid plaques and mitochondrial viscosity with different fluorescence wavelength signals "turn-on" at around 624 and 640 nm, respectively. Moreover, the staining of brain sections from a transgenic AD mouse showed that probe C25e showed higher selectivity and signal-to-noise ratio towards Aß plaques than commercially-available Thio-S. In addition, the probe C25e was, for the first time, employed for monitoring amyloid-ß induced mitochondrial viscosity changes. Therefore, this GFP-based red-emissive fluorescent probe C25e could serve as a dual-functional tool for imaging ß-amyloid plaques and mitochondrial viscosity, which might provide a unique strategy for the early diagnosis of Alzheimer's disease.

Increased α-2,6 sialic acid on microglia in amyloid pathology is resistant to oseltamivir.

Terminal sialic acid residues are present on most glycoproteins and glycolipids, but levels of sialylation are known to change in the brain throughout the lifespan as well as during disease. Sialic acids are important for numerous cellular processes including cell adhesion, neurodevelopment, and immune regulation as well as pathogen invasion into host cells. Neuraminidase enzymes, also known as sialidases, are responsible for removal of terminal sialic acids in a process known as desialylation. Neuraminidase 1 (Neu1) cleaves the α-2,6 bond of terminal sialic acids. Aging individuals with dementia are often treated with the antiviral medication oseltamivir, which is associated with induction of adverse neuropsychiatric side effects; this drug inhibits both viral and mammalian Neu1. The present study tested whether a clinically relevant antiviral dosing regimen of oseltamivir would disrupt behavior in the 5XFAD mouse model of Alzheimer's disease amyloid pathology or wild-type littermates. While oseltamivir treatment did not impact mouse behavior or modify amyloid plaque size or morphology, a novel spatial distribution of α-2,6 sialic acid residues was discovered in 5XFAD mice that was not present in wild-type littermates. Further analyses revealed that α-2,6 sialic acid residues were not localized the amyloid plaques but instead localized to plaque-associated microglia. Notably, treatment with oseltamivir did not alter α-2,6 sialic acid distribution on plaque-associated microglia in 5XFAD mice which may be due to downregulation of Neu1 transcript levels in 5XFAD mice. Overall, this study suggests that plaque-associated microglia are highly sialylated and are resistant to change with oseltamivir, thus interfering with microglia immune recognition of and response to amyloid pathology.

The amyloid-ß pathway in Alzheimer's disease: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This plain language summary of an article published in Molecular Psychiatry, reviews the evidence supporting the role of the amyloid-ß (Aß) pathway and its dysregulation in Alzheimer's disease (AD), and highlights the rationale for drugs targeting the Aß pathway in the early stages of the disease. WHY IS THIS IMPORTANT?: Aß is a protein fragment (or peptide) that exists in several forms distinguished by their size, shape/structure, degree of solubility and disease relevance. The accumulation of Aß plaques is a hallmark of AD. However, smaller, soluble aggregates of Aß - including Aß protofibrils - also play a role in the disease. Because Aß-related disease mechanisms are complex, the diagnosis, treatment and management of AD should be reflective of and guided by up-to-date scientific knowledge and research findings in this area. This article describes the Aß protein and its role in AD, summarizing the evidence showing that altered Aß clearance from the brain may lead to the imbalance, toxic buildup and misfolding of the protein - triggering a cascade of cellular, molecular and systematic events that ultimately lead to AD. WHAT ARE THE KEY TAKEAWAYS?: The physiological balance of brain Aß levels in the context of AD is complex. Despite many unanswered questions, mounting evidence indicates that Aß has a central role in driving AD progression. A better understanding of the Aß pathway biology will help identify the best therapeutic targets for AD and inform treatment approaches.

Herbal Therapeutics for Alzheimer's Disease: Ancient Indian Medicine System from the Modern Viewpoint.

Alzheimer's is a chronic neurodegenerative disease where amyloid-beta (Aß) plaques and neurofibrillary tangles are formed inside the brain. It is also characterized by progressive memory loss, depression, neuroinflammation, and derangement of other neurotransmitters. Due to its complex etiopathology, current drugs have failed to completely cure the disease. Natural compounds have been investigated as an alternative therapy for their ability to treat Alzheimer's disease (AD). Traditional herbs and formulations which are used in the Indian ayurvedic system are rich sources of antioxidant, anti-amyloidogenic, neuroprotective, and anti-inflammatory compounds. They promote quality of life by improving cognitive memory and rejuvenating brain functioning through neurogenesis. A rich knowledge base of traditional herbal plants (Turmeric, Gingko, Ashwagandha, Shankhpushpi, Giloy, Gotu kola, Garlic, Tulsi, Ginger, and Cinnamon) combined with modern science could suggest new functional leads for Alzheimer's drug discovery. In this article Ayurveda, the ancient Indian herbal medicine system based on multiple clinical and experimental, evidence have been reviewed for treating AD and improving brain functioning. This article presents a modern perspective on the herbs available in the ancient Indian medicine system as well as their possible mechanisms of action for AD treatment. The main objective of this research is to provide a systematic review of herbal drugs that are easily accessible and effective for the treatment of AD.

Synthesis and In Vitro and In Vivo Evaluation of 18F-Labeled Positron Emission Tomography Tracers for Imaging Aß Plaques.

Accurate quantification of amyloid beta (Aß) plaques is an important indicator for Alzheimer's disease diagnosis and treatment. For this purpose, new highly sensitive Aß tracers were designed by regulating the position and number of nitrogen atoms. A series of derivatives of florbetapir (AV45) containing different numbers and positions of N atoms were synthesized and evaluated for in vitro affinity and in vivo biodistribution. Preliminary study results showed that [18F]BIBD-124 and [18F]BIBD-127 had better clearance rates and less in vivo defluorination than AV45 in ICR (ICR = Institute of Cancer Research) mice. Autoradiography and molecular docking indicated that the binding sites of [18F]BIBD-124/127 were similar to that of [18F]AV45. Micro-positron emission tomography-computed tomography imaging further demonstrated that [18F]BIBD-124 could monitor Aß plaques similar to [18F]AV45. Besides, the imaging contrast of [18F]BIBD-124 is better than that of [18F]AV45. Mass spectrometric metabolic analysis showed that BIBD-124 was less demethylated than AV45 without subsequent acetylation, which might explain its less non-specific uptake and higher imaging contrast. Gauss calculations further confirmed that the introduction of N5 in [18F]BIBD-124 decreased demethylation. Considering imaging contrast and in vivo defluorination, [18F]BIBD-124 is expected to be a promising radiotracer of Aß plaques for further clinical trials.

Tactile stimulation improves cognition, motor, and anxiety-like behaviors and attenuates the Alzheimer's disease pathology in adult APPNL-G-F/NL-G-F mice.

Alzheimer's disease (AD) is one of the largest health crises in the world. There are limited pharmaceutical interventions to treat AD, however, and most of the treatment options are not for cure or prevention, but rather to slow down the progression of the disease. The aim of this study was to examine the effect of tactile stimulation (TS) on AD-like symptoms and pathology in APPNL-G-F/NL-G-F mice, a mouse model of AD. The results show that TS reduces the AD-like symptoms on tests of cognition, motor, and anxiety-like behaviors and these improvements in behavior are associated with reduced AD pathology in APP mice. Thus, TS appears to be a promising noninvasive strategy for slowing the onset of dementia in aging animals.

Quantitative proteomics of tau and Aß in detergent fractions from Alzheimer's disease brains.

The two hallmarks of Alzheimer's disease (AD) are amyloid-ß (Aß) plaques and neurofibrillary tangles marked by phosphorylated tau. Increasing evidence suggests that aggregating Aß drives tau accumulation, a process that involves synaptic degeneration leading to cognitive impairment. Conversely, there is a realization that non-fibrillar (oligomeric) forms of Aß mediate toxicity in AD. Fibrillar (filamentous) aggregates of proteins across the spectrum of the primary and secondary tauopathies were the focus of recent structural studies with a filament structure-based nosologic classification, but less emphasis was given to non-filamentous co-aggregates of insoluble proteins in the fractions derived from post-mortem human brains. Here, we revisited sarkosyl-soluble and -insoluble extracts to characterize tau and Aß species by quantitative targeted mass spectrometric proteomics, biochemical assays, and electron microscopy. AD brain sarkosyl-insoluble pellets were greatly enriched with Aß42 at almost equimolar levels to N-terminal truncated microtubule-binding region (MTBR) isoforms of tau with multiple site-specific post-translational modifications (PTMs). MTBR R3 and R4 tau peptides were most abundant in the sarkosyl-insoluble materials with a 10-fold higher concentration than N-terminal tau peptides. This indicates that the major proportion of the enriched tau was the aggregation-prone N-terminal and proline-rich region (PRR) of truncated mixed 4R and 3R tau with more 4R than 3R isoforms. High concentration and occupancies of site-specific phosphorylation pT181 (~22%) and pT217 (~16%) (key biomarkers of AD) along with other PTMs in the PRR and MTBR indicated a regional susceptibility of PTMs in aggregated tau. Immunogold labelling revealed that tau may exist in globular non-filamentous form (N-terminal intact tau) co-localized with Aß in the sarkosyl-insoluble pellets along with tau filaments (N-truncated MTBR tau). Our results suggest a model that Aß and tau interact forming globular aggregates, from which filamentous tau and Aß emerge. These characterizations contribute towards unravelling the sequence of events which lead to end-stage AD changes.

Glutamate's Effects on the N-Methyl-D-Aspartate (NMDA) Receptor Ion Channel in Alzheimer's Disease Brain: Challenges for PET Radiotracer Development for Imaging the NMDA Ion Channel.

In an effort to further understand the challenges facing in vivo imaging probe development for the N-methyl-D-aspartate (NMDA) receptor ion channel, we have evaluated the effect of glutamate on the Alzheimer's disease (AD) brain. Human post-mortem AD brain slices of the frontal cortex and anterior cingulate were incubated with [3H]MK-801 and adjacent sections were tested for Aß and Tau. The binding of [3H]MK-801 was measured in the absence and presence of glutamate and glycine. Increased [3H]MK-801 binding in AD brains was observed at baseline and in the presence of glutamate, indicating a significant increase (>100%) in glutamate-induced NMDA ion channel activity in AD brains compared to cognitively normal brains. The glycine effect was lower, suggesting a decrease of the co-agonist effect of glutamate and glycine in the AD brain. Our preliminary findings suggest that the targeting of the NMDA ion channel as well as the glutamate site may be appropriate in the diagnosis and treatment of AD. However, the low baseline levels of [3H]MK-801 binding in the frontal cortex and anterior cingulate in the absence of glutamate and glycine indicate significant hurdles for in vivo imaging probe development and validation.

Design, synthesis, and preliminary evaluation of [18F]-aryl flurosulfates PET radiotracers via SuFEx methods for ß-amyloid plaques in Alzheimer's disease.

[18F]BAY-94-9172, [18F]AV-45, and [18F]GE-067 were FDA approved positron emission tomography (PET) imaging radiotracer of ß-amyloid plaques (Aß) in Alzheimer's disease (AD). However, the radiochemical synthesis requires multi-step reactions and complex procedure. Recently, a protocol for radiochemical synthesis of sulfur fluoride exchange (SuFEx) using ultrafast 19F/18F isotopic exchange had been reported. We developed three pairs of novel 18F-labeled radiotracers by the "SuFEx" method for PET imaging Aß plaques. The 18F labeling reaction can be completed quickly (30 s) at room temperature and purified using solid-phase extraction (SPE). The radiochemical purity (RCP) of the products was all greater than 95 %. In vitro fluorescent staining using Aß-transgenesis mice section preliminary verified the affinity of tracers with Aß. Competitive binding assay displayed high affinity of tracers for towards artificial Aß1-42 aggregates (Ki values ranging from 3.53 ± 0.39 to 42.0 ± 4.24 nM). In vivo biodistribution and Micro-PET imaging showed that [18F]-Sulfur Fluoride ß-Amyloid ([18F]SFA 1-6) could penetration the blood-brain barrier (BBB) in wild-type mice, and [18F]SFA 5-6 had a high initial brain uptake value (3.65 ± 0.9 % and 5.07 ± 0.1 % ID/g, respectively) and a fast washout (Brain uptake2 min/60 min = 4.15 and 4.61, respectively) from the brain. In vitro autoradiography demonstrated the affinity of the [18F]SFA 5-6 to Aß plaques in AD human brain tissues. Our results suggested that [18F]SFA maybe a potential PET radiotracers for detecting Aß in Alzheimer's disease.

Rational design of molecular rotor-based fluorescent probes with bi-aromatic rings for efficient in vivo detection of amyloid-ß plaques in Alzheimer's disease.

The presence of Aß plaques in the brain is a hallmark of Alzheimer's disease. Here, we designed and synthesized a series of molecular rotors with various bi-aromatic rings and investigated their applications as near-infrared (NIR) probes for Aß plaques. We found that the interaction with Aß aggregates hindered the rotational freedom of the molecular rotors, which brought about a noticeable enhancement in fluorescence intensity. Among them, probe 4b (Kd = 8.5 nM) with a phenyl-pyridine ring showed a 98-fold increase in fluorescence intensity upon binding with Aß aggregates. In addition, 4b could identify Aß plaques in brain sections of both a transgenic (Tg) mouse and AD patients. Furthermore, 4b could readily penetrate the mouse blood-brain barrier (brain2min = 10.11% ID/g) and washed out rapidly. Finally, the NIR imaging with Tg mice confirmed the practical application of 4b in detecting Aß plaques in vivo. Altogether, our work widens the landscape of Aß NIR probes and offers a new tool for Aß detection.