Alzheimer's Plaques Research Articles

Synthesis of Novel Pyrazolo[3,4-b]pyridines with Affinity for β-Amyloid Plaques

Three novel pyrazolo[3,4-b]pyridines were synthesized via the cyclization of 5-amino-1-phenylpyrazole with the corresponding unsaturated ketone in the catalytic presence of ZrCl4. The ketones were afforded by modifying a stabilized ylide facilitated Wittig reaction in fairly high yields. The novel compounds exhibited exciting photophysical properties with the dimethylamine phenyl-bearing pyrazolopyridine showing exceptionally large Stoke’s shifts. Finally, both the dimethylamino- and the pyrene-substituted compounds demonstrated high and selective binding to amyloid plaques of Alzheimer’s disease (AD) patient brain slices upon fluorescent confocal microscopy observation. These results reveal the potential application of pyrazolo[3,4-b]pyridines in the development of AD amyloid plaque probes of various modalities for AD diagnosis.

PLCG2 is associated with the inflammatory response and is induced by amyloid plaques in Alzheimer\u2019s disease

BackgroundAlzheimer’s disease (AD) is characterized by robust microgliosis and phenotypic changes that accompany disease pathogenesis. Accumulating evidence from genetic studies suggests the importance of phospholipase C γ 2 (PLCG2) in late-onset AD (LOAD) pathophysiology. However, the role of PLCG2 in AD is still poorly understood.MethodsUsing bulk RNA-Seq (N=1249) data from the Accelerating Medicines Partnership-Alzheimer’s Disease Consortium (AMP-AD), we investigated whether PLCG2 expression increased in the brains of LOAD patients. We also evaluated the relationship between PLCG2 expression levels, amyloid plaque density, and expression levels of microglia specific markers (AIF1 and TMEM119). Finally, we investigated the longitudinal changes of PLCG2 expression in the 5xFAD mouse model of AD. To further understand the role of PLCG2 in different signaling pathways, differential gene expression and co-expression network analyses were performed using bulk RNA-Seq and microglial single-cell RNA-Seq data. To substantiate the human analyses, we performed differential gene expression analysis on wild-type (WT) and inactivated Plcg2 mice and used immunostaining to determine if the differentially expressed genes/pathways were altered by microglial cell coverage or morphology.ResultsWe observed significant upregulation of PLCG2 expression in three brain regions of LOAD patients and significant positive correlation of PLCG2 expression with amyloid plaque density. These findings in the human brain were validated in the 5xFAD amyloid mouse model, which showed disease progression-dependent increases in Plcg2 expression associated with amyloid pathology. Of note, increased Plcg2 expression levels in 5xFAD mice were abolished by reducing microglia. Furthermore, using bulk RNA-Seq data, we performed differential expression analysis by comparing cognitively normal older adults (CN) with 75th percentile (high) and 25th percentile (low) PLCG2 gene expression levels to identify pathways related to inflammation and the inflammatory response. The findings in the human brain were validated by differential expression analyses between WT and plcg2 inactivated mice. PLCG2 co-expression network analysis of microglial single-cell RNA-Seq data identified pathways related to the inflammatory response including regulation of I-kappaB/NF-kappa B signaling and response to lipopolysaccharide.ConclusionsOur results provide further evidence that PLCG2 plays an important role in AD pathophysiology and may be a potential target for microglia-targeted AD therapies.

Does Soluble TREM2 Protect Against Alzheimer's Disease?

Triggering Receptor Expressed in Myeloid Cells 2 (TREM2) is a pattern recognition receptor on myeloid cells, and is upregulated on microglia surrounding amyloid plaques in Alzheimer's disease (AD). Rare, heterozygous mutations in TREM2 (e.g., R47H) increase AD risk several fold. TREM2 can be cleaved at the plasma membrane by metalloproteases to release the ectodomain as soluble TREM2 (sTREM2). Wild-type sTREM2 binds oligomeric amyloid beta (Aβ) and acts as an extracellular chaperone, blocking and reversing Aβ oligomerization and fibrillization, and preventing Aβ-induced neuronal loss in vitro. Whereas, R47H sTREM2 increases Aβ fibrillization and neurotoxicity. AD brains expressing R47H TREM2 have more fibrous plaques with more neuritic pathology around these plaques, consistent with R47H sTREM2 promoting Aβ fibrillization relative to WT sTREM2. Brain expression or injection of wild-type sTREM2 reduces pathology in amyloid models of AD in mice, indicating that wild-type sTREM2 is protective against amyloid pathology. Levels of sTREM2 in cerebrospinal fluid (CSF) fall prior to AD, rise in early AD, and fall again in late AD. People with higher sTREM2 levels in CSF progress more slowly into and through AD than do people with lower sTREM2 levels, suggesting that sTREM2 protects against AD. However, some of these experiments can be interpreted as full-length TREM2 protecting rather than sTREM2, and to distinguish between these two possibilities, we need more experiments testing whether sTREM2 itself protects in AD and AD models, and at what stage of disease. If sTREM2 is protective, then treatments could be designed to elevate sTREM2 in AD.

Evaluation of Styrylbenzene analog- FSB and its affinity to bind parenchymal plaques and tangles in patients of Alzheimer's disease.

Although several histochemical markers for senile plaques (SP) and neurofibrillary tangles (NFTs) have been synthesized since the discovery of plaques in Alzheimer's disease (AD), only a handful of these markers stain both lesions in the human brain. Despite discovery of its ability to stain both SP and NFT over 13years ago, the styrylbenzene derivative, (E,E)-1-fluoro-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (FSB), has only recently gained attention, primarily due to its ability to function as a contrasting agent for MRI imaging of AD pathology in vivo. The structure of the compound is a nuclide with quantized angular momentum, which explains its value as a contrast agent. In the current study, modification of the established staining procedure produced meaningful improvement in the labeling of plaques and tangles in the human brain. We utilized two rodent models of AD to show FSB's value in labeling both Aβ and tau lesions. Furthermore, our current modification allows us to detect SP in rodent brains in 15min and both SP and NFT in human brains within 20min. The study presents new evidence regarding potential binding targets for FSB as well as optimization protocols in which various parameters have been manipulated to show how section thickness, use of frozen versus paraffin-embedded sections, and selection of staining media can affect the intensity of the plaque and tangle staining in the brain. To determine the target FSB potentially binds, we performed double immunolabeling of FSB with mOC64 (a conformational antibody that label Aβ1-42). Results indicated that all plaques in the brain colocalized with mOC64, suggesting that FSB has the potential to bind all Aβ containing plaques, making it a very sensitive detector of multiple forms of SP... All antibodies were assessed for the degree of colocalization with FSB in order to better understand potential binding targets. We found more than 90% hyperphosphorylated Tau against AT8, AT180 and S214 colocalized with FSB labeled tangles. On the other hand, more than 90% of the mOC64 containing plaques colocalized with FSB stained plaques. Our results indicate that FSB is a valuable marker that can be used to detect AD pathologies in human and rodent brains with greater fluorescence intensity relative to other conventional fluorescence markers.

Intranasal neprilysin rapidly eliminates amyloid-beta plaques, but causes plaque compensations: the explanation why the amyloid-beta cascade may fail?

Neurodegenerative brain disorders are a major burden in our society, such as Alzheimer´s disease. In order to repair or prevent such diseases, drugs are designed which enter the brain, but the blood-brain barrier limits their entry and the search for alternative pathways is important. Recently, we reported that intranasal delivery of the amyloid-beta degrading enzyme neprilysin eliminated amyloid-beta plaques in transgenic Alzheimer´s disease mice. This review describes the anatomical structure of the intranasal pathway, explains the intranasal delivery of pure neprilysin, cell-loaded neprilysin (platelets) and collagen-embedded neprilysin to destruct amyloid-beta plaques in Alzheimer´s disease in transgenic APP_SweDI mice and hypothesizes why this may cause compensation and why the amyloid-beta cascade hypothesis may fail.

Define and visualize pathological architectures of human tissues from spatially resolved transcriptomics using deep learning

Spatially resolved transcriptomics provides a new way to define spatial contexts and understand the pathogenesis of complex human diseases. Although some computational frameworks can characterize spatial context via various clustering methods, the detailed spatial architectures and functional zonation often cannot be revealed and localized due to the limited capacities of associating spatial information. We present RESEPT, a deep-learning framework for characterizing and visualizing tissue architecture from spatially resolved transcriptomics. Given inputs such as gene expression or RNA velocity, RESEPT learns a three-dimensional embedding with a spatial retained graph neural network from spatial transcriptomics. The embedding is then visualized by mapping into color channels in an RGB image and segmented with a supervised convolutional neural network model. Based on a benchmark of 10x Genomics Visium spatial transcriptomics datasets on the human and mouse cortex, RESEPT infers and visualizes the tissue architecture accurately. It is noteworthy that, for the in-house AD samples, RESEPT can localize cortex layers and cell types based on pre-defined region- or cell-type-enriched genes and furthermore provide critical insights into the identification of amyloid-beta plaques in Alzheimer's disease. Interestingly, in a glioblastoma sample analysis, RESEPT distinguishes tumor-enriched, non-tumor, and regions of neuropil with infiltrating tumor cells in support of clinical and prognostic cancer applications.

Structural amyloid plaque polymorphism is associated with distinct lipid accumulations revealed by trapped ion mobility mass spectrometry imaging.

Understanding of Alzheimer's disease (AD) pathophysiology requires molecular assessment of how key pathological factors, specifically amyloid β (Aβ) plaques, influence the surrounding microenvironment. Here, neuronal lipids have been implicated in Aβ plaque pathology, though the lipid microenvironment in direct proximity to Aβ plaques is still not fully resolved. A further challenge is the microenvironmental molecular heterogeneity, across structurally polymorphic Aβ features, such as diffuse, immature, and mature, fibrillary aggregates, whose resolution requires the integration of advanced, multimodal chemical imaging tools. Herein, we used matrix-assisted laser desorption/ionization trapped ion mobility spectrometry time-of-flight based mass spectrometry imaging (MALDI TIMS TOF MSI) in combination with hyperspectral confocal microscopy to probe the lipidomic microenvironment associated with structural polymorphism of Aβ plaques in transgenic Alzheimer's disease mice (tgAPPSWE ). Using on tissue and ex situ validation, TIMS MS/MS facilitated unambiguous identification of isobaric lipid species that showed plaque pathology-associated localizations. Integrated multivariate imaging data analysis revealed multiple, Aβ plaque-enriched lipid patterns for gangliosides (GM), phosphoinositols (PI), phosphoethanolamines (PE), and phosphatidic acids (PA). Conversely, sulfatides (ST), cardiolipins (CL), and polyunsaturated fatty acid (PUFA)-conjugated phosphoserines (PS), and PE were depleted at plaques. Hyperspectral amyloid imaging further delineated the unique distribution of PA and PE species to mature plaque core regions, while PI, LPI, GM2 and GM3lipids localized to immature Aβ aggregates present within the periphery of Aβ plaques. Finally, we followed AD pathology-associated lipid changes over time, identifying plaque- growth and maturation to be characterized by peripheral accumulation of PI (18:0/22:6). Together, these data demonstrate the potential of multimodal imaging approaches to overcome limitations associated with conventional advanced MS imaging applications. This allowed for the differentiation of both distinct lipid components in a complex micro-environment as well as their correlation to disease-relevant amyloid plaque polymorphs. Cover Image for this issue: https://doi.org/10.1111/jnc.15390.

Modulating physicochemical properties of tetrahydropyridine-2-amine BACE1 inhibitors with electron-withdrawing groups: A systematic study

A common challenge for medicinal chemists is to reduce the pKa of strongly basic groups' conjugate acids into a range that preserves the desired effects, usually potency and/or solubility, but avoids undesired effects like high volume of distribution (Vd), limited membrane permeation, and off-target binding to, notably, the hERG channel and monoamine receptors. We faced this challenge with a 3,4,5,6-tetrahydropyridine-2-amine scaffold harboring an amidine, a key structural component of potential inhibitors of BACE1, the rate-limiting enzyme in the production of Aβ species that make up amyloid plaques in Alzheimer's disease. In our endeavor to balance potency with desirable properties to achieve brain penetration, we introduced a diverse set of groups in beta position of the amidine that modulate logD, PSA and pKa. Given the synthetic challenge to prepare these highly functionalized warheads, we first developed a design flow including predicted physicochemical parameters which allowed us to select only the most promising candidates for synthesis. For this we evaluated a set of commercial packages to predict physicochemical properties, which can guide medicinal chemists in their endeavors to modulate pKa values of amidine and amine bases.

Quantifying patterns of pathology: A characterization of the 3D spatial distribution of tau tangles and amyloid plaques in Alzheimer’s disease using multi‐modal image registration with a scattering transform

AbstractBackgroundVolumetric measures of MRI scans have consistently shown medial temporal lobe (MTL) atrophy in individuals across the spectrum of AD. However, these measures are not considered to be specific for AD, partly because a direct link to tau and amyloid pathology has not been demonstrated (Jack et. al, 2018). To address this limitation, we developed multi‐modal image registration and analysis tools to integrate neuropathological data from 2D histology images with 3D postmortem MRI images in the same brain region, in order to quantify the density of tangles and plaques.MethodsWe imaged tissue excised from the MTL at 0.125 mm resolution with an 11T MR scanner (fig 1a) and manually segmented it into subregions (fig 1b). We sliced the tissue into 10um thick sections, 1mm apart, and digitally imaged them with a light microscope after staining for amyloid (6E10) or tau (PHF‐1) (fig 1c). Locations of tangles and plaques on histology were estimated with a deep convolutional neural network (UNET) trained on a smaller set of annotated data (fig 1d). To align histology images with the MRI images, we first computed scattering transforms of histology to capture high resolution textural information (fig 1e). This was then used to find both optimal spatial and intensity profile transformations between the two imaging modalities (fig 1f). We rigidly aligned MRI images to the Mai Paxinos atlas for interpretability.ResultsWe localized tau tangles and amyloid plaques from histology sections of a person with severe AD, and in corresponding 3D MRI images of the brain tissue from the same individual. We quantified density of particles per region. Initial findings demonstrated the highest amount of tau in the entorhinal cortex, subiculum, and CA1 (fig 2) compared to other subregions in the MTL, consistent with Braak staging. No obvious differential distribution of amyloid was observed.ConclusionOur detailed localization of tangles and plaques in 3D offers the opportunity to study spatial distribution of pathology within brain regions among patients that span the spectrum of disease, which will foster more robust comparison with MRI atrophy, and potentially shed new light on the progression of AD.

Molecular and Therapeutic Targets for Amyloid-beta Plaques in Alzheimer's Disease: A Review Study.

Alzheimer's disease (AD) is characterized by progressive loss of cognition and a gradual decrease in memory. Although AD is considered the most persistent form of dementia and a global concern, no complete cure or agents that can completely halt the progression of AD have been found. In the past years, significant progress has been made in understanding the cellular and molecular changes associated with AD, and numerous drug targets have been identified for the development of drugs for this disease. Amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFT) are the major attributes of AD. Symptomatic relief is the only possible treatment available at present and a disease-modifying drug is of utmost importance. The development of drugs that can inhibit different targets responsible for the formation of plaques is a potential area in AD research. This review is not a complete list of all possible targets for AD but serves to highlight the targets related to Aβ pathology and pathways concerned with the formation of Aβ fragments. This shall serve as a prospect in the identification of Aβ plaque inhibitors and pave the strategies for newer drug treatments. Nevertheless, substantial research is done in this area but to bridle, the clinical difficulty remains a concern.

Cofilin Signaling in the CNS Physiology and Neurodegeneration.

All eukaryotic cells are composed of the cytoskeleton, which plays crucial roles in coordinating diverse cellular functions such as cell division, morphology, migration, macromolecular stabilization, and protein trafficking. The cytoskeleton consists of microtubules, intermediate filaments, and actin filaments. Cofilin, an actin-depolymerizing protein, is indispensable for regulating actin dynamics in the central nervous system (CNS) development and function. Cofilin activities are spatiotemporally orchestrated by numerous extra- and intra-cellular factors. Phosphorylation at Ser-3 by kinases attenuate cofilin’s actin-binding activity. In contrast, dephosphorylation at Ser-3 enhances cofilin-induced actin depolymerization. Cofilin functions are also modulated by various binding partners or reactive oxygen species. Although the mechanism of cofilin-mediated actin dynamics has been known for decades, recent research works are unveiling the profound impacts of cofilin dysregulation in neurodegenerative pathophysiology. For instance, oxidative stress-induced increase in cofilin dephosphorylation is linked to the accumulation of tau tangles and amyloid-beta plaques in Alzheimer’s disease. In Parkinson’s disease, cofilin activation by silencing its upstream kinases increases α-synuclein-fibril entry into the cell. This review describes the molecular mechanism of cofilin-mediated actin dynamics and provides an overview of cofilin’s importance in CNS physiology and pathophysiology.

The signal peptide of the amyloid precursor protein forms amyloid-like aggregates and enhances Aβ42 aggregation

Signal sequences are short peptides at the N terminus of proteins destined for the secretion pathway. Typically, after cleavage by peptidases, signal peptides are degraded by intra-membrane proteases. In some cases, however, signal peptides can be processed further and released into the endoplasmic reticulum, secretion pathways, or cytoplasm. The consequences of these processes remain unclear, in particular considering that dysregulated signal peptides could potentially aggregate and induce cytotoxicity. To investigate this problem, we study the signal peptide of the amyloid precursor protein (APP), which originates the Alzheimer’s β-amyloid (Aβ) peptide. Our results show that this signal peptide (residues 1–17 of APP [APP 1–17 SP]) can form amyloid-like cytotoxic aggregates. We further demonstrate that APP 1–17 SP seeds promote aggregation of Aβ, which raises the intriguing possibility of an interplay between APP 1–17 SP and Aβ aggregation in disease processes. The signal peptide of APP (APP 1–17 SP) self-assembles into amyloid-like aggregates APP 1–17 SP aggregates exhibit amyloid-like morphologies in SEM, TEM, and AFM APP 1–17 SP aggregates are cytotoxic to human SH-SY5Y and red blood cells APP 1–17 SP seeds augment Aβ42 aggregation Protein aggregation is associated with the pathogenesis of several human diseases. Gadhave et al. report that the signal peptide of the amyloid precursor protein (APP) can self-assemble into cytotoxic amyloid-like aggregates and enhance aggregation of the β-amyloid (Aβ) peptide, which forms amyloid plaques in Alzheimer’s disease.

Aducanumab and the “post-amyloid” era of Alzheimer research?

Aducanumab and the “post-amyloid” era of Alzheimer research?

Cross-Seeded Fibrillation Induced by Pyroglutamate-3 and Truncated Aβ40 Variants Leads to Aβ40 Structural Polymorphism Modulation and Elevated Toxicity.

The pathological amyloid plaques in Alzheimer's disease (AD) patients contain not only the wild-type β-amyloid (wt-Aβ) peptide sequences but also a variety of post-translationally modified variants. The pyroglutamate-3 Aβ (pyroE3-Aβ), which is generated from its truncated precursors ΔE3-Aβ, shows the highest abundance among all modified Aβ variants. Previous works have shown that pyroE3-Aβ and/or ΔE3-Aβ, compared with the wild-type sequences, led to a more rapid fibrillation process and final fibrils with higher neuronal cytotoxicity levels. However, much less is known about how the formation of pyroE3/ΔE3-Aβ fibrils would affect the amyloid deposition of wt-Aβ peptides, which are the main pathological events in AD. We show in the present work that the pyroE3/ΔE3-Aβ40 fibrils differ significantly from the wt-Aβ40 fibrils in terms of their molecular structures. When added into monomeric wt-Aβ40 peptides, these variant fibrils can cross-seed the formation of wt-Aβ40 fibrils with fibrillation kinetics that are greater than the self-seeded fibrillation of wt-Aβ40. Furthermore, the cross-seeding process modulates the molecular structures of the yielded wt-Aβ40 fibrils, which show similar features as their variant seeds. The cross-seeded fibrillation process also induces higher cytotoxicity levels compared with the self-seeded fibrillation of wt-Aβ40. Overall, our results support the hypothesis that pyroE3 and ΔE3-Aβ40 variants may serve as triggering factors of the pathological amyloid aggregation of wt-Aβ40 and may underlie the pathological significance of pyroE3/ΔE3-Aβ40 variants on the structural polymorphism of Aβ deposits.

Neuroprotective potential of berberine in modulating Alzheimer's disease via multiple signaling pathways.

Berberine is one of the most important quinoline alkaloids, which has shown numerous pharmacological activities. There are pieces of evidence that berberine serves as a promising substance for treating Alzheimer's disease (AD). Recently, numerous studies on animal models have shown the neuroprotective role of berberine. AD is a complex disease having multiple pathological factors. Berberine restrains the deposition of amyloid plaques and neurofibrillary tangles. Substantial studies have demonstrated that berberine may also exhibit the protective effect against the risk factors associated with AD. This review illustrates the role of berberine in neuroinflammation, oxidative stress and its activity against acetylcholinesterase enzyme. It also focuses on the bioavailability and safety of berberine in AD. However, more investigations are required to explore the bioavailability and safety assessment of berberine and its new perspectives in limiting the AD-related pathogenesis and risk factors. PRACTICAL APPLICATIONS: Current therapeutic measures only provide symptomatic relief against AD by slowing memory loss, resolving thinking problems and behavioral issues. In recent past years, many biological actions and potential therapeutic applications have been observed by berberine particularly in neurological diseases. Berberine has been investigated by various researchers for its activity against AD. This review demonstrates a variety of mechanisms by which berberine imparts its neuroprotective roles and provides the possible mechanism of action of berberine by which it prevents the formation of neurofibrillary tangles and disaggregation of amyloid beta plaques in AD. It also focuses that berberine limits the neuroinflammation and oxidative stress in AD. Pre-clinical aspects of berberine against AD are also discussed. Eventually, a prospect is formulated that berberine might be a therapeutically significant agent for treating and preventing AD.

Citrullination of Amyloid-β Peptides in Alzheimer's Disease.

Protein citrullination (deimination of arginine residue) is a well-known biomarker of inflammation. Elevated protein citrullination has been shown to colocalize with extracellular amyloid plaques in postmortem AD patient brains. Amyloid-β (Aβ) peptides which aggregate and accumulate in the plaques of Alzheimer's disease (AD) have sequential N-terminal truncations and multiple post-translational modifications (PTM) such as isomerization, pyroglutamate formation, phosphorylation, nitration, and dityrosine cross-linking. However, no conclusive biochemical evidence exists whether citrullinated Aβ is present in AD brains. In this study, using high-resolution mass spectrometry, we have identified citrullination of Aβ in sporadic and familial AD brains by characterizing the tandem mass spectra of endogenous N-truncated citrullinated Aβ peptides. Our quantitative estimations demonstrate that ∼ 35% of pyroglutamate3-Aβ pool was citrullinated in plaques in the sporadic AD temporal cortex and ∼ 22% in the detergent-insoluble frontal cortex fractions. Similarly, hypercitrullinated pyroglutamate3-Aβ (∼ 30%) was observed in both the detergent-soluble as well as insoluble Aβ pool in familial AD cases. Our results indicate that a common mechanism for citrullination of Aβ exists in both the sporadic and familial AD. We establish that citrullination of Aβ is a remarkably common PTM, closely associated with pyroglutamate3-Aβ formation and its accumulation in AD. This may have implications for Aβ toxicity, autoantigenicity of Aβ, and may be relevant for the design of diagnostic assays and therapeutic targeting.

Effects of microglial depletion and TREM2 deficiency on A\u03b2 plaque burden and neuritic plaque tau pathology in 5XFAD mice

Dystrophic neuronal processes harboring neuritic plaque (NP) tau pathology are found in association with Aβ plaques in Alzheimer’s disease (AD) brain. Microglia are also in proximity to these plaques and microglial gene variants are known risk factors in AD, including loss-of-function variants of TREM2. We have further investigated the role of Aβ plaque-associated microglia in 5XFAD mice in which NP tau pathology forms after intracerebral injection of AD brain-derived pathologic tau (AD-tau), focusing on the consequences of reduced TREM2 expression and microglial depletion after treatment with the colony-stimulating factor 1 (CSFR1) inhibitor, PLX3397. Young 5XFAD mice treated with PLX3397 had a large reduction of brain microglia, including cortical plaque-associated microglia, with a significant reduction of Aβ plaque burden in the cortex. A corresponding decrease in cortical APP-positive dystrophic processes and NP tau pathology were observed after intracerebral AD-tau injection in the PLX3397-treated 5XFAD mice. Consistent with prior reports, 5XFAD × TREM2−/− mice showed a significant reduction of plaque-associated microglial, whereas 5XFAD × TREM2+/− mice had significantly more plaque-associated microglia than 5XFAD × TREM2−/− mice. Nonetheless, AD-tau injected 5XFAD × TREM2+/− mice showed greatly increased AT8-positive NP tau relative to 5XFAD × TREM2+/+ mice. Expression profiling revealed that 5XFAD × TREM2+/− mice had a disease-associated microglial (DAM) gene expression profile in the brain that was generally intermediate between 5XFAD × TREM2+/+ and 5XFAD × TREM2−/− mice. Microarray analysis revealed significant differences in cortical and hippocampal gene expression between AD-tau injected 5XFAD × TREM2+/− and 5XFAD × TREM2−/− mice, including pathways linked to microglial function. These data suggest there is not a simple correlation between the extent of microglia plaque interaction and plaque-associated neuritic damage. Moreover, the differences in gene expression and microglial phenotype between TREM2+/− and TREM2−/− mice suggest that the former may better model the single copy TREM2 variants associated with AD risk.

A literature review of MRI techniques used to detect amyloid-beta plaques in Alzheimer’s disease patients

In this review, we aim to provide an overview of the imaging techniques most commonly used to study Alzheimer's disease (AD). Neuroimaging biomarkers can be used to evaluate these abnormalities, improve the ability of early diagnosis and help predict disease progression. These signs mainly include local brain atrophy on structural MRI, hypometabolic foci, and amyloid plaque deposition in the brain detected by specific imaging. These techniques not only have their unique advantages, but can complement each other in multimodal imaging evaluation of patients with cognitive impairment and dementia. A literature search was performed on PubMed using the search term combinations "Alzheimer's disease", "Amyloid-beta plaques", and "MRI". We discuss various magnetic resonance imaging (MRI) based techniques, including direct imaging, indirect imaging, amyloid-beta (Aβ) plaque and radiomics, Hybrid PET/MRI and MRI imaging technology in the future, placing a special emphasis on multimodal imaging, and focus our review on the MRI features of Aβ plaques (AD biomarkers). After a lot of research and reasonable selection, multimodal imaging composed of MRI and PET can significantly improve the diagnosis and treatment of AD patients, and the complementary information can be obtained by the new PET/MR instrument at the same time. The findings of this review emphasize that multimodal imaging is likely to be the preferred method for future AD research and clinical practice.

A Triphenylamine Derivative-based Fluorescent Probe with Good Water Solubility for Targeting Aβ Plaques in Alzheimer’s Disease

A Triphenylamine Derivative-based Fluorescent Probe with Good Water Solubility for Targeting Aβ Plaques in Alzheimer’s Disease

Optical Imaging of Beta-Amyloid Plaques in Alzheimer's Disease.

Alzheimer’s disease (AD) is a multifactorial, irreversible, and incurable neurodegenerative disease. The main pathological feature of AD is the deposition of misfolded β-amyloid protein (Aβ) plaques in the brain. The abnormal accumulation of Aβ plaques leads to the loss of some neuron functions, further causing the neuron entanglement and the corresponding functional damage, which has a great impact on memory and cognitive functions. Hence, studying the accumulation mechanism of Aβ in the brain and its effect on other tissues is of great significance for the early diagnosis of AD. The current clinical studies of Aβ accumulation mainly rely on medical imaging techniques, which have some deficiencies in sensitivity and specificity. Optical imaging has recently become a research hotspot in the medical field and clinical applications, manifesting noninvasiveness, high sensitivity, absence of ionizing radiation, high contrast, and spatial resolution. Moreover, it is now emerging as a promising tool for the diagnosis and study of Aβ buildup. This review focuses on the application of the optical imaging technique for the determination of Aβ plaques in AD research. In addition, recent advances and key operational applications are discussed.