Isotope Encoded Spatial Biology Identifies Amyloid Plaque-Age-Dependent Structural Maturation, Synaptic Loss, and Increased Toxicity.

Understanding how amyloid beta (Aβ) plaques form and progress to neurotoxicity in Alzheimer's disease remains a significant challenge. This study aims to elucidate the processes involved in Aβ plaque formation and maturation using a knock-in Aβ mouse model ( ). By employing mass spectrometry imaging and stable isotope labeling, we timestamped Aβ plaques from their initial deposition, enabling the spatial tracking of plaque aging.

Soluble cerebral Aβ protofibrils link Aβ plaque pathology to changes in CSF Aβ/Aβ ratios, neurofilament light and tau in Alzheimer's disease model mice.

The Aβ/Aβ ratio in the cerebrospinal fluid (CSF) and the concentrations of neurofilament light (NfL) and total tau (t-tau) are changed in the early stages of Alzheimer's disease (AD), but their neurobiological correlates are not entirely understood. Here, we used 5xFAD transgenic mice to investigate the associations between these CSF biomarkers and measures of cerebral Aβ, including Aβ/Aβ ratios in plaques, insoluble fibrillar deposits and soluble protofibrils. A high Aβ/Aβ ratio in soluble protofibrils was the strongest independent predictor of low CSF Aβ/Aβ ratios and high CSF NfL and t-tau concentrations when compared to Aβ/Aβ ratios in plaques and insoluble fibrillar deposits.

Levetiracetam prevents Aβ production through SV2a-dependent modulation of App processing in Alzheimer's disease models.

In Alzheimer's disease (AD), amyloid-beta (Aβ) peptides are produced by proteolytic cleavage of the amyloid precursor protein (APP), which can occur during synaptic vesicle (SV) cycling at presynapses. Precisely how amyloidogenic APP processing may impair presynaptic proteostasis and how to therapeutically target this process remains poorly understood. Using knock-in mouse models of early Aβ pathology, we found proteins with hampered degradation accumulate at presynaptic sites.

Isotope Encoded chemical Imaging Identifies Amyloid Plaque Age Dependent Structural Maturation, Synaptic Loss, and Increased Toxicity.

It is of critical importance to our understanding of Alzheimer's disease (AD) pathology to determine how key pathological factors are interconnected and implicated in nerve cell death, clinical symptoms, and disease progression. The formation of extracellular beta-amyloid (Aβ) plaques is the major pathological hallmark of AD and Aβ has been suggested to be a critical inducer of AD, driving disease pathogenesis. Exactly how Aβ plaque formation begins and how ongoing plaque deposition proceeds and initiates subsequent neurotoxic mechanisms is not well understood.

Chemical signatures delineate heterogeneous amyloid plaque populations across the Alzheimer's disease spectrum.

Amyloid plaque deposition is recognized as the primary pathological hallmark of Alzheimer's disease(AD) that precedes other pathological events and cognitive symptoms. Plaque pathology represents itself with an immense polymorphic variety comprising plaques with different stages of amyloid fibrillization ranging from diffuse to fibrillar, mature plaques. The association of polymorphic Aβ plaque pathology with AD pathogenesis, clinical symptoms and disease progression remains unclear.

Thiophene-Based Ligands for Specific Assignment of Distinct Aβ Pathologies in Alzheimer's Disease.

Aggregated species of amyloid-β (Aβ) are one of the pathological hallmarks in Alzheimer's disease (AD), and ligands that selectively target different Aβ deposits are of great interest. In this study, fluorescent thiophene-based ligands have been used to illustrate the features of different types of Aβ deposits found in AD brain tissue. A dual-staining protocol based on two ligands, HS-276 and LL-1, with different photophysical and binding properties, was developed and applied on brain tissue sections from patients affected by sporadic AD or familial AD associated with the mutation.

Spatial Neurolipidomics at the Single Amyloid-β Plaque Level in Postmortem Human Alzheimer's Disease Brain.

Lipid dysregulations have been critically implicated in Alzheimer's disease (AD) pathology. Chemical analysis of amyloid-β (Aβ) plaque pathology in transgenic AD mouse models has demonstrated alterations in the microenvironment in the direct proximity of Aβ plaque pathology. In mouse studies, differences in lipid patterns linked to structural polymorphism among Aβ pathology, such as diffuse, immature, and mature fibrillary aggregates, have also been reported.

Correlative Chemical Imaging and Spatial Chemometrics Delineate Alzheimer Plaque Heterogeneity at High Spatial Resolution.

We present a novel, correlative chemical imaging strategy based on multimodal matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI), hyperspectral microscopy, and spatial chemometrics. Our workflow overcomes challenges associated with correlative MSI data acquisition and alignment by implementing 1 + 1-evolutionary image registration for precise geometric alignment of multimodal imaging data and their integration in a common, truly multimodal imaging data matrix with maintained MSI resolution (10 μm). This enabled multivariate statistical modeling of multimodal imaging data using a novel multiblock orthogonal component analysis approach to identify covariations of biochemical signatures between and within imaging modalities at MSI pixel resolution.

Tetramodal Chemical Imaging Delineates the Lipid-Amyloid Peptide Interplay at Single Plaques in Transgenic Alzheimer's Disease Models.

Beta-amyloid (Aβ) plaque pathology is one of the most prominent histopathological feature of Alzheimer's disease (AD). The exact pathogenic mechanisms linking Aβ to AD pathogenesis remain however not fully understood. Recent advances in amyloid-targeting pharmacotherapies highlight the critical relevance of Aβ aggregation for understanding the molecular basis of AD pathogenesis.

Chemical traits of cerebral amyloid angiopathy in familial British-, Danish-, and non-Alzheimer's dementias.

Familial British dementia (FBD) and familial Danish dementia (FDD) are autosomal dominant forms of dementia caused by mutations in the integral membrane protein 2B (ITM2B, also known as BRI2) gene. Secretase processing of mutant BRI2 leads to secretion and deposition of BRI2-derived amyloidogenic peptides, ABri and ADan that resemble APP/β-amyloid (Aβ) pathology, which is characteristic of Alzheimer's disease (AD). Amyloid pathology in FBD/FDD manifests itself predominantly in the microvasculature by ABri/ADan containing cerebral amyloid angiopathy (CAA).

Correlative Chemical Imaging Identifies Amyloid Peptide Signatures of Neuritic Plaques and Dystrophy in Human Sporadic Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease. The predominantly sporadic form of AD is age-related, but the underlying pathogenic mechanisms remain not fully understood. Current efforts to combat the disease focus on the main pathological hallmarks, in particular beta-amyloid (Aβ) plaque pathology.

Unveiling spatial metabolome of Paeonia suffruticosa and Paeonia lactiflora roots using MALDI MS imaging.

Paeonia suffruticosa (PS) and Paeonia lactiflora (PL) belong to the only genus in the family Paeoniaceae. Comparative analysis of the spatial metabolomes of PS and PL has rarely been performed. In this work, combined with multiple matrixes and dual-polarity detection, high mass resolution matrix-assisted laser desorption/ionization MS imaging (MALDI MSI) and MALDI tandem MSI were performed on the root sections of the two Paeonia species.

3-Aminophthalhydrazide (Luminol) As a Matrix for Dual-Polarity MALDI MS Imaging.

In many aspects of the matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) technique, the discovery of new MALDI matrixes has been a major task for the improvement of ionization efficiency, signal intensity, and molecular coverage. In this work, five analog compounds, including phthalhydrazide, 3-aminophthalhydrazide (3-APH or luminol) and its sodium salt, 4-aminophthalhydrazide (4-APH), and 3-nitrophthalhydrazide (3-NPH) were evaluated as potential matrixes for MALDI Fourier-transform ion cyclotron resonance (FTICR) MSI of metabolites in mouse brain tissue. The five candidate MALDI matrixes were mainly evaluated according to the solid-state ultraviolet absorption, the ion yields and species, and the dual-polarity detection.

Quantitative MALDI Imaging of Spatial Distributions and Dynamic Changes of Tetrandrine in Multiple Organs of Rats.

Detailed spatio-temporal information on drug distribution in organs is of paramount importance to assess drug clinically-relevant properties and potential side-effects. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) as a label-free and sensitive imaging modality provides an additional means of accurately visualizing drug and its metabolites distributions in tissue sections. However, technical limitations, complex physiochemical environment of surface and low abundance of target drugs make quantitative MALDI imaging of drug and its metabolites quite challenging.

Sample preparation for mass spectrometry imaging of leaf tissues: a case study on analyte delocalization.

Appropriate sample preparation is pivotally important to obtain high-quality mass spectrometry imaging (MSI) data. Unlike mammalian tissues, preparation of cryosections from plant tissues for MSI measurement is quite challenging due to its intrinsic complex texture and cellular structure. This is especially true for leaf samples which are generally thin, water-rich, and fragile.

Interrogation of spatial metabolome of Ginkgo biloba with high-resolution matrix-assisted laser desorption/ionization and laser desorption/ionization mass spectrometry imaging.

Ginkgo biloba is one of the oldest extant seed plants and has a number of unique properties and uses. Numerous efforts have characterized metabolites within the ginkgo plant and their corresponding biosynthesis pathways, but spatio-chemical information on ginkgo metabolites is lacking. Mass spectrometry (MS) imaging was used to interrogate the spatio-chemical localization of metabolites with matrix-assisted laser desorption/ionization and laser desorption/ionization Fourier-transform ion cyclotron resonance MS across the ginkgo leaf.