Single-nucleus multi-omics analyses reveal cellular and molecular innovations in the anterior cingulate cortex during primate evolution.

The anterior cingulate cortex (ACC) of the human brain is involved in higher-level cognitive functions such as emotion and self-awareness. We generated profiles of human and macaque ACC gene expression and chromatin accessibility at single-nucleus resolution. We characterized the conserved patterns of gene expression, chromatin accessibility, and transcription factor binding in different cell types.

Synthesis and preclinical evaluation of diarylamine derivative as Tau-PET radiotracer for Alzheimer's Disease.

The presence of aggregated Tau in the brain is a dominant pathological hallmark of Tauopathies, particularly in Alzheimer's disease (AD). Therefore, developing ligands that can specifically and sensitively bind to Tau aggregates is essential for diagnosing and monitoring therapeutic interventions. In this study, we further investigated the structural optimization of the diarylamine skeleton, which exhibited promising binding characteristics and biological properties.

Discovery and Evaluation of Imidazo[2,1-][1,3,4]thiadiazole Derivatives as New Candidates for α-Synuclein PET Imaging.

α-synuclein (α-syn) pathologies are central to the development of synucleinopathies including Parkinson's disease (PD). Positron emission tomography (PET) imaging of α-syn pathologies is one strategy to facilitate the diagnosis, understanding, and treatment of synucleinopathies, but has been restricted by the lack of specific α-syn PET probes. In this work, we identified 2,6-disubstituted imidazo[2,1-][1,3,4]thiadiazole (ITA) as a new α-syn-binding scaffold.

Reduced biophotonic activities and spectral blueshift in Alzheimer's disease and vascular dementia models with cognitive impairment.

Background: Although clinically, Alzheimer's disease (AD) and vascular dementia (VaD) are the two major types of dementia, it is unclear whether the biophotonic activities associated with cognitive impairments in these diseases share common pathological features.

Methods: We used the ultraweak biophoton imaging system (UBIS) and synaptosomes prepared by modified percoll method to directly evaluate the functional changes in synapses and neural circuits in AD and VaD model animals.

Results: We found that biophotonic activities induced by glutamate were significantly reduced and spectral blueshifted in synaptosomes and brain slices.

Hydroxyethyl-Modified Cycloheptatriene-BODIPY Derivatives as Specific Tau Imaging Probes.

Near-infrared fluorescence (NIRF) imaging as an exquisite sensitive, high spatial-resolution, and real-time tool plays an important role in visualizing pathologies in the brain. In this study, we designed and synthesized a series of NIR probes of hydroxyethyl cycloheptatriene-BODIPY derivatives that have demonstrated strong binding specificity to native neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brain sections. The improved hydrophilicity of and resulted in faster clearance rates from healthy brains (4.

Synthesis and Preclinical Evaluation of 2-(4-[F]Fluorophenyl)imidazo[1,2-h][1,7]naphthyridine ([F]FPND-4): An Aza-Fused Tricyclic Derivative as Positron Emission Tomography Tracer for Neurofibrillary Tangle Imaging.

Tau accumulation is one of the predominant neuropathological biomarkers for diagnosis of Alzheimer's disease due to its high correlation with disease progression. In this study, we focused on the structure-activity relationship study of the substituent effect on the aza-fused tricyclic core imidazo[1,2-h][1,7]naphthyridine to screen F-labeled Tau tracers. Through a series of autoradiographic studies and biological evaluations, 4-[F]fluorophenyl-substituted tracer [F] ([F]) was identified as a promising candidate with high affinity to native Tau tangles (IC = 2.

Fluorine-18-Labeled Diaryl-azines as Improved β-Amyloid Imaging Tracers: From Bench to First-in-Human Studies.

The deposition of β-amyloid (Aβ) in the brain is a pathologic hallmark of Alzheimer's disease (AD), appearing years before the onset of symptoms, and its detection is incorporated into clinical diagnosis. Here, we have discovered and developed a class of diaryl-azine derivatives for detecting Aβ plaques in the AD brain using PET imaging. After a set of comprehensive preclinical assessments, we screened out a promising Aβ-PET tracer, [F], with a high binding affinity to the Aβ aggregates, significant binding ability with the AD brain sections, and optimal brain pharmacokinetic properties in rodents and non-human primates.

Compact Luminol Chemiluminophores for In Vivo Detection and Imaging of β-Sheet Protein Aggregates.

Protein aggregation has been found in a wide range of neurodegenerative protein-misfolding diseases. The demand for in vivo technologies to identify protein aggregation is at the leading edge for the pathogenic study, diagnostic development, and therapeutic intervention of these devastating disorders. Herein, we report a series of luminol analogues to construct a facile chemiluminescence (CL)-based approach for in vivo detection and imaging of β-sheet protein aggregates.

Discovery and evaluation of aza-fused tricyclic derivatives for detection of Tau pathology in Alzheimer's disease.

For various neurodegenerative diseases, including Alzheimer's disease (AD), the abnormal aggregation of Tau is not only the predominant contributing factor but also a major biomarker for disease diagnosis. In this study, a series of aza-fused tricyclic derivatives were designed and synthesized. By changing the position and number of nitrogen atoms on the fused tricyclic core, the imidazonaphthyridine scaffold was screened and reported for the first time which could potentially detect Tau aggregates.

Fused Cycloheptatriene-BODIPY Is a High-Performance Near-Infrared Probe to Image Tau Tangles.

Neurofibrillary tangles (NFTs), which are composed of abnormally hyperphosphorylated Tau, are one of the main pathologic hallmarks of Alzheimer's disease and other tauopathies. The fluorescent imaging probes currently used to target NFTs cannot distinguish them well from β-amyloid plaques, thus limiting their utility to diagnose diseases. Here, we developed a fused cycloheptatriene-BODIPY derivative () that displays properties favorable for near-infrared (NIR) imaging with high affinity and specificity to NFTs .

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

The presence of Aβ 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 Aβ plaques. We found that the interaction with Aβ aggregates hindered the rotational freedom of the molecular rotors, which brought about a noticeable enhancement in fluorescence intensity.

Severe tauopathy and axonopathy in the medulla oblongata in Alzheimer's disease implicate the changes in autonomic nervous function.

The autonomic dysfunctions in Alzheimer's disease (AD) have been identified from many clinical studies, however, there is still a lack of evidence directly verifying the structural abnormalities of the autonomic nervous system in AD. Human medulla oblongatas from four AD patients or five non-AD subjects were obtained and observed by using immunohistochemical staining of hyperphosphorylated tau and Aβ amyloid, and post-mortem tracing techniques. We found distinct axonal and somatic immunoreactivities for the tau markers AT8 and Tau-5 in the different areas of the medulla oblongata in AD patients, which was particularly obvious in the dorsal nucleus of the vagus nerve, the nucleus of the solitary tract and the reticular nucleus.

Biophoton imaging identification of delayed functional neural circuit injury after cerebral ischemia-reperfusion.

Background: The evaluation of structural changes after stroke has made great progress; however, it remains difficult to evaluate functional neural changes.

New Method: Here, we report a novel imaging technique that could monitor delayed functional neural circuit injury in an animal model of cerebral ischemia-reperfusion. The changes in 50 mM glutamate-induced biophotonic activities in functional neural circuits in rat brain slices after middle cerebral artery occlusion were investigated with an ultraweak biophoton imaging system.

SNP rs10420324 in the AMPA receptor auxiliary subunit TARP γ-8 regulates the susceptibility to antisocial personality disorder.

In the brain, AMPA receptors mediate fast excitatory neurotransmission, the dysfunction of which leads to neuropsychiatric disorders. Synaptic function of AMPA receptors is tightly controlled by a protein group called transmembrane AMPAR regulatory proteins (TARPs). TARP γ-8 (also known as CACNG8) preferentially expresses in the hippocampus, cortex and subcortical regions that are critical for emotion generation indicating its association with psychiatric disorders.

Quantum energy levels of glutamate modulate neural biophotonic signals.

Glutamate is the most abundant excitatory neurotransmitter in the brain, and it plays an essential and important role in neural functions. Current studies have shown that glutamate can induce neural biophotonic activity and transmission, which may involve the mechanism of photon quantum brain; however, it is unclear whether such a mechanism follows the principle of quantum mechanics. Here we show that the action of glutamate on its receptors leads to a decrease in its quantum energy levels, and glutamate then partially or completely loses its function to further induce the biophotonic activity in mouse brain slices.

Synthesis and Evaluation of Fluorine-18 Labeled 2-Phenylquinoxaline Derivatives as Potential Tau Imaging Agents.

In this study, three pairs of optically pure F-labeled 2-phenylquinoxaline derivatives were evaluated as Tau imaging agents for the diagnosis of Alzheimer's disease (AD). The chiral 2-fluoromethyl-1,2-ethylenediol side chain was attached to the 2-phenylquinoxaline backbone to increase hydrophilicity, thereby improving the binding affinity of the probe to tangles and their selectivity toward Tau tangles over β-amyloid plaques (Aβ). These probes displayed excellent fluorescent properties and high selectivity for tangles on brain sections from transgenic mice (rTg4510) and AD patients.

Near-Infrared Fluorescent Probes with Rotatable Polyacetylene Chains for the Detection of Amyloid-β Plaques.

The plaques of accumulated β-amyloid (Aβ) in the parenchymal brain are accepted as an important biomarker for the early diagnosis of Alzheimer's disease (AD). Many near-infrared (NIR) probes, which were based on the D-π-A structure and bridged by conjugated double bonds, had been reported and displayed a high affinity to Aβ plaques. Considering the isomerization caused by the polyethylene chain, however, the conjugated polyacetylene chain is a better choice for developing new NIR Aβ probes.

Spectral blueshift of biophotonic activity and transmission in the ageing mouse brain.

The brain is considered to be a complex system with extremely low energy consumption and high-efficiency information transmission and processing, and this system has not been replicated by any artificial systems so far. Several studies indicate that the activity and transmission of biophotons in neural circuits may play an important role in neural information communication, while the biophotonic spectral redshift from lower to higher in animals may be related to the evolution of intelligence. The ageing processes of higher organisms are often accompanied by a decline in brain functions; however, the underlying mechanisms are unclear.

Discovery of Diphenoxy Derivatives with Flexible Linkers as Ligands for β-Amyloid Plaques.

The highly rigid and planar scaffolds with π-conjugated systems have been widely considered to be indispensable for β-amyloid (Aβ) binding ligands. In this study, a library of diphenoxy compounds with different types of more flexible linkers as Aβ ligands were synthesized and evaluated. Most of them displayed good affinity ( < 100 nM) for Aβ aggregates, and some ligands even showed values of less than 10 nM.

N,O-Benzamide difluoroboron complexes as near-infrared probes for the detection of β-amyloid and tau fibrils.

In this study, a series of organo difluoroboron probes with a BF2 benzamide moiety was designed, prepared and evaluated. Among them, 2c displayed the best optical and biological properties, and may be used as a useful near-infrared fluorescent probe for the detection of Aβ plaques and neurofibrillary tangles in AD.

Folium Sennae and emodin reverse airway smooth muscle contraction.

The objective of this project was to find a bronchodilatory compound from herbs and clarify the mechanism. We found that the ethanol extract of Folium Sennae (EEFS) can relax airway smooth muscle (ASM). EEFS inhibited ASM contraction, induced by acetylcholine, in mouse tracheal rings and lung slices.

Paracetamol inhibits Ca permeant ion channels and Ca sensitization resulting in relaxation of precontracted airway smooth muscle.

The purpose of this study was to screen a bronchodilator from old drugs and elucidate the underlying mechanism. Paracetamol (acetaminophen) is a widely used analgesic and antipyretic drug. It has been reported that it inhibits the generation of prostaglandin and histamine, which play roles in asthma.

The depression GWAS risk allele predicts smaller cerebellar gray matter volume and reduced SIRT1 mRNA expression in Chinese population.

Major depressive disorder (MDD) is recognized as a primary cause of disability worldwide, and effective management of this illness has been a great challenge. While genetic component is supposed to play pivotal roles in MDD pathogenesis, the genetic and phenotypic heterogeneity of the illness has hampered the discovery of its genetic determinants. In this study, in an independent Han Chinese sample (1824 MDD cases and 3031 controls), we conducted replication analyses of two genetic loci highlighted in a previous Chinese MDD genome-wide association study (GWAS), and confirmed the significant association of a single nucleotide polymorphism (SNP) rs12415800 near SIRT1.