Disease Mouse Brain Research Articles

Identification of tauopathy-associated lipid signatures in Alzheimer’s disease mouse brain using label-free chemical imaging

There is cumulative evidence that lipid metabolism plays a key role in the pathogenesis of various neurodegenerative disorders including Alzheimer’s disease (AD). Visualising lipid content in a non-destructive label-free manner can aid in elucidating the AD phenotypes towards a better understanding of the disease. In this study, we combined multiple optical molecular-specific methods, Fourier transform infrared (FTIR) spectroscopic imaging, synchrotron radiation-infrared (SR-IR) microscopy, Raman and stimulated Raman scattering (SRS) microscopy, and optical-photothermal infrared (O-PTIR) microscopy with multivariate data analysis, to investigate the biochemistry of brain hippocampus in situ using a mouse model of tauopathy (rTg4510). We observed a significant difference in the morphology and lipid content between transgenic (TG) and wild type (WT) samples. Immunohistochemical staining revealed some degree of microglia co-localisation with elevated lipids in the brain. These results provide new evidence of tauopathy-related dysfunction in a preclinical study at a subcellular level.

Spatially and temporally probing distinctive glycerophospholipid alterations in Alzheimer’s disease mouse brain via high-resolution ion mobility-enabled sn-position resolved lipidomics

Dysregulated glycerophospholipid (GP) metabolism in the brain is associated with the progression of neurodegenerative diseases including Alzheimer’s disease (AD). Routine liquid chromatography-mass spectrometry (LC-MS)-based large-scale lipidomic methods often fail to elucidate subtle yet important structural features such as sn-position, hindering the precise interrogation of GP molecules. Leveraging high-resolution demultiplexing (HRdm) ion mobility spectrometry (IMS), we develop a four-dimensional (4D) lipidomic strategy to resolve GP sn-position isomers. We further construct a comprehensive experimental 4D GP database of 498 GPs identified from the mouse brain and an in-depth extended 4D library of 2500 GPs predicted by machine learning, enabling automated profiling of GPs with detailed acyl chain sn-position assignment. Analyzing three mouse brain regions (hippocampus, cerebellum, and cortex), we successfully identify a total of 592 GPs including 130 pairs of sn-position isomers. Further temporal GPs analysis in the three functional brain regions illustrates their metabolic alterations in AD progression.

A novel NIR fluorescent probe for copper(ii) imaging in Parkinson's disease mouse brain.

Abnormal copper ion (Cu2+) levels are considered to be one of the pathological factors of Parkinson's disease (PD), but the internal relationship between Cu2+ and PD progression remains elusive. Visualizing Cu2+ in the brain will be pivotal for comprehending the underlying pathophysiological processes of PD. In this work, a near-infrared (NIR) fluorescent probe, DDAO-Cu, capable of detecting Cu2+ with exceptional sensitivity (about 1.8 nM of detection limit) and selectivity, rapid response (<3 min), and deep tissue penetration, was designed for quantification and visualization of the Cu2+ level. It could detect not only Cu2+ in cells but also the changes in the Cu2+ level in the rotenone-induced cell and zebrafish PD models. Moreover, DDAO-Cu can cross the blood-brain barrier to image Cu2+ in the brain of PD model mice. The imaging result showed a significant increase in Cu2+ levels in brain regions of PD model mice, including the cerebral cortex, hippocampus, and striatum. Meanwhile, Cu2+ levels in the substantia nigra region were significantly reduced in PD model mice. It revealed the nuanced relationship of Cu2+ levels in different brain regions in the disease and indicated the pathological complexity of PD. Overall, DDAO-Cu represents a novel and practical tool for investigating Cu2+-related physiological and pathological processes underlying Parkinson's disease.

CHRISTMAS: Chiral Pair Isobaric Labeling Strategy for Multiplexed Absolute Quantitation of Enantiomeric Amino Acids.

Amino acids (AAs) in the d-form are involved in multiple pivotal neurological processes, although their l-enantiomers are most commonly found. Mass spectrometry-based analysis of low-abundance d-AAs has been hindered by challenging enantiomeric separation from l-AAs, low sensitivity for detection, and lack of suitable internal standards for accurate quantification. To address these critical gaps, N,N-dimethyl-l-leucine (l-DiLeu) tags are first validated as novel chiral derivatization reagents for chromatographic separation of 20 pairs of d/l-AAs, allowing the construction of a 4-plex isobaric labeling strategy for enantiomer-resolved quantification through single step tagging. Additionally, the creative design of N,N-dimethyl-d-leucine (d-DiLeu) reagents offers an alternative approach to generate analytically equivalent internal references of d-AAs using d-DiLeu-labeled l-AAs. By labeling cost-effective l-AA standards using paired d- and l-DiLeu, this approach not only enables absolute quantitation of both d-AAs and l-AAs from complex biological matrices with enhanced precision but also significantly boosts the combined signal intensities from all isobaric channels, greatly improving the detection and quantitation of low-abundance AAs, particularly d-AAs. We term this quantitative strategy CHRISTMAS, which stands for chiral pair isobaric labeling strategy for multiplexed absolute quantitation. Leveraging the ion mobility collision cross section (CCS) alignment, interferences from coeluting isomers/isobars are effectively filtered out to provide improved quantitative accuracy. From wild-type and Alzheimer's disease (AD) mouse brains, we successfully quantified 20 l-AAs and 5 d-AAs. The significant presence and differential trends of certain d-AAs compared to those of their l-counterparts provide valuable insights into the involvement of d-AAs in aging, AD progression, and neurodegeneration.

Isotope dilution LA-ICP-MS for quantitative imaging of trace elements in mouse brain sections

Isotope dilution (ID) analysis is considered one of the most accurate quantitative methods. However, it has not been widely applied to the quantitative imaging of trace elements in biological samples using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS), mainly because of difficulties in homogeneously mixing enriched isotopes (the spike) with the sample (e.g., a tissue section). In this study, we present a novel method for the quantitative imaging of trace elements (copper and zinc) in mouse brain sections using ID-LA-ICP-MS. We used an electrospray-based coating device (ECD) to evenly distribute a known amount of the spike (65Cu and 67Zn) on the sections. The optimal conditions for this process involved evenly distributing the enriched isotopes on mouse brain sections mounted on indium tin oxide (ITO) glass slides using the ECD with the 10 mg g−1 ɑ-cyano-4-hydroxycinnamic acid (CHCA) in methanol at 80 °C. The mass of the spiked isotopes and the tissue sections on the ITO slides was calculated by weighing them on an analytical balance. Quantitative images of Cu and Zn in Alzheimer's disease (AD) mouse brain sections were obtained using ID-LA-ICP-MS. These imaging results showed that Cu and Zn concentrations in various brain regions typically ranged from 10 to 25 μg g−1 and 30–80 μg g−1, respectively. But it is worth noting that the hippocampus contained up to 50 μg g−1 of Zn, while the cerebral cortex and hippocampus had Cu contents as high as 150 μg g−1. These results were validated by acid digestion and solution analysis with ICP-MS. The novel ID-LA-ICP-MS method provides an accurate and reliable means for quantitative imaging of biological tissue sections.

Simultaneous Fe2+/Fe3+ imaging shows Fe3+ over Fe2+ enrichment in Alzheimer's disease mouse brain.

Visualizing redox-active metal ions, such as Fe2+ and Fe3+ ions, are essential for understanding their roles in biological processes and human diseases. Despite the development of imaging probes and techniques, imaging both Fe2+ and Fe3+ simultaneously in living cells with high selectivity and sensitivity has not been reported. Here, we selected and developed DNAzyme-based fluorescent turn-on sensors that are selective for either Fe2+ or Fe3+, revealing a decreased Fe3+/Fe2+ ratio during ferroptosis and an increased Fe3+/Fe2+ ratio in Alzheimer's disease mouse brain. The elevated Fe3+/Fe2+ ratio was mainly observed in amyloid plaque regions, suggesting a correlation between amyloid plaques and the accumulation of Fe3+ and/or conversion of Fe2+ to Fe3+. Our sensors can provide deep insights into the biological roles of labile iron redox cycling.

Blood–Brain Barrier Permeable Photoacoustic Probe for High-Resolution Imaging of Nitric Oxide in the Living Mouse Brain

Alternations in the brain nitric oxide (NO) homeostasis are associated with a variety of neurodegeneration diseases; therefore, high-resolution imaging of NO in the brain is essential for understanding pathophysiological processes. However, currently available NO probes are unsuitable for this purpose due to their poor ability to cross the blood-brain barrier (BBB) or to image in deep tissues with spatial resolution. Herein, we developed a photoacoustic (PA) probe with BBB crossing ability to overcome this obstacle. The probe shows a highly selective ratiometric response toward NO, which enables the probe to image NO with micron resolution in the whole brain of living mice. Using three-dimensional PA imaging, we demonstrated that the probe could be used to visualize the detailed NO distribution in varying depth cross-sections (0-8 mm) of the living Parkinson's disease (PD) mouse brain. We also investigated the therapeutic properties of natural polyphenols in the PD mouse brain using the probe as an imaging agent and suggested the potential of the probe for screening therapeutic agents. This study provides a promising imaging agent for imaging of NO in the mouse brain with high resolution. We anticipate that these findings may open up new possibilities for understanding the biological functions of NO in the brain and the development of new imaging agents for the diagnosis and treatment of brain diseases.

Region-specific heterogeneity in neuronal nuclear morphology in young, aged and in Alzheimer's disease mouse brains.

Neurons in the mammalian brain exhibit enormous structural and functional diversity across different brain regions. Compared to our understanding of the morphological diversity of neurons, very little is known about the heterogeneity of neuronal nuclear morphology and how nuclear size changes in aging and diseased brains. Here, we report that the neuronal cell nucleus displays differences in area, perimeter, and circularity across different anatomical regions in the mouse brain. The pyramidal neurons of the hippocampal CA3 region exhibited the largest area whereas the striatal neuronal nuclei were the smallest. These nuclear size parameters also exhibited dichotomous changes with age across brain regions-while the neocortical and striatal neurons showed a decrease in nuclear area and perimeter, the CA3 neurons showed an increase with age. The nucleus of parvalbumin- and calbindin-positive interneurons had comparable morphological features but exhibited differences between brain regions. In the context of activity-dependent transcription in response to a novel environment, there was a decrease in nuclear size and circularity in c-Fos expressing neurons in the somatosensory cortex and hippocampal CA1 and CA3. In an APP/PS1 mutant mouse model of Alzheimer's disease (AD), the neuronal nuclear morphology varies with plaque size and with increasing distance from the plaque. The neuronal nuclear morphology in the immediate vicinity of the plaque was independent of the plaque size and the morphology tends to change away from the plaque. These changes in the neuronal nuclear size and shape at different ages and in AD may be attributed to changes in transcriptional activity. This study provides a detailed report on the differences that exist between neurons in nuclear morphology and can serve as a basis for future studies.

Efficient Electrochemical Microsensor for In Vivo Monitoring of H2O2 in PD Mouse Brain: Rational Design and Synthesis of Recognition Molecules

Hydrogen peroxide (H2O2), one of the most stable and abundant reactive oxygen species (ROS), acting as a modulator of dopaminergic signaling, has been intimately implicated in Parkinson's disease, creating a critical need for the selective quantification of H2O2 in the living brain. Current natural or nanomimic enzyme-based electrochemical methods employed for the determination of H2O2 suffer from inadequate selectivity and stability, due to which the in vivo measurement of H2O2 in the living brain remains a challenge. Herein, a series of 5-(1,2-dithiolan-3-yl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pentanamide (DBP) derivatives were designed by tuning the substitute groups and sites of a boric acid ester, which served as probes to specifically react with H2O2. Consequently, the reaction products, 5-(1,2-dithiolan-3-yl)-N-(4-hydroxyphen-yl)pentanamide (DHP) derivatives, converted the electrochemical signal from inactive into active. After systematically evaluating their performances, 5-(1,2-dithiolan-3-yl)-N-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pentanamide (o-Cl-DBP) was finally identified as the optimized probe for H2O2 detection as it revealed the fastest reaction time, the largest current density, and the most negative potential. In addition, electrochemically oxidized graphene oxide (EOGO) was utilized to produce a stable inner reference. The designed electrochemical microsensor provided a ratiometric strategy for real-time tracking of H2O2 in a linear range of 0.5-600 μM with high selectivity and accuracy. Eventually, the efficient electrochemical microsensor was successfully applied to the measurement of H2O2 in Parkinson's disease (PD) mouse brain. The average levels of H2O2 in the cortex, striatum, and hippocampus in the normal mouse and PD mouse were systematically compared for the first time.

Reduced dopaminergic neuron degeneration and global transcriptional changes in Parkinson's disease mouse brains engrafted with human neural stems during the early disease stage

IntroductionCurrent stem cell therapies for Parkinson's disease (PD) focus on a neurorestorative approach that aims to repair the CNS during the symptomatic phase. However, the pleiotropic and supportive effects of human neural stem cells (hNSCs) may make them effective for PD treatment during the disease's earlier stages. In the current study, we investigated the therapeutic effects of transplanting hNSCs during the early stages of PD development when most dopaminergic neurons are still present and before symptoms appear. Previous studies on hNSCs in Parkinson's disease focus on the substantia nigra and its immediate surroundings, but other brain structures are affected in PD as well. Here, we investigated the therapeutic effects of hNSCs on the entire PD-afflicted brain transcriptome using RNA sequencing (RNA-seq). MethodsPD was induced with a single intranasal infusion of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and hNSCs were transplanted unilaterally into the striatum one week later. The timepoint for hNSC transplantation coincided with upregulation of endogenous proinflammatory cytokines in the CNS, which play a role in stem cell migration. At 3 weeks post-transplantation (4 weeks post-MPTP), we assessed motor symptoms through behavioral tests, quantified dopaminergic neurons in the substantia nigra, and performed global transcriptional profiling to understand the mechanism underlying the effect of hNSCs on dopaminergic neuron degeneration. ResultsWe found that early hNSC engraftment mitigated motor symptoms induced by MPTP, and also reduced MPTP-induced loss of dopaminergic neurons. In this study, we uniquely presented the first comprehensive analysis of the effect of hNSC transplantation on the transcriptional profiling of PD mouse brains showing decreased expression of 249 and increased expression of 200 genes. These include genes implicated in mitochondrial bioenergetics, proteostasis, and other signaling pathways associated with improved PD outcome following hNSC transplantation. ConclusionThese findings indicate that NSC transplantation during the asymptomatic phase of PD may limit or halt the progression of this neurodegenerative disorder. Transcriptional profiling of hNSC-engrafted PD mouse brains provides mechanistic insight that could lead to novel approaches to ameliorating degeneration of dopaminergic neurons and improving behavioral dysfunction in PD.

Spatial proteomic alterations detected via MALDI-MS imaging implicate neuronal loss in a Huntington's disease mouse (YAC128) brain.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that occurs with the increase of CAG trinucleotide repeats in the huntingtin gene. To understand the mechanisms of HD, powerful proteomics techniques, such as liquid chromatography-tandem mass spectrometry (LC-MS/MS) were employed. However, one major drawback of these methods is loss of the region-specific quantitative information of the proteins due to analysis of total tissue lysates. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) is a MS-based label-free technique that works directly on tissue sections and gathers m/z values with their respective regional information. In this study, we established a data processing protocol that includes several software programs and methods to determine spatial protein alterations between the brain samples of a 12 month-old YAC128 HD mouse model and their non-transgenic littermates. 22 differentially expressed proteins were revealed with their respective regional information, and possible relationships of several proteins were discussed. As a validation of the MALDI-MSI analysis, a differentially expressed protein (GFAP) was verified using immunohistochemical staining. Furthermore, since several proteins detected in this study have previously been associated with neuronal loss, neuronal loss in the cortical region was demonstrated using an anti-NeuN immunohistochemical staining method. In conclusion, the findings of this research have provided insights into the spatial proteomic changes between HD transgenic and non-transgenic littermates and therefore, we suggest that MALDI-MSI is a powerful technique to determine spatial proteomic alterations between biological samples, and the data processing that we present here can be employed as a complementary tool for the data analysis.

A two-photon ratiometric fluorescent probe for real-time imaging and quantification of NO in neural stem cells during activation regulation.

Developing a novel tool capable of real-time monitoring and accurate quantification of NO is critical to understanding its role in physiological and pathological processes. Herein, a two-photon ratiometric fluorescent probe (NOP) was developed for real-time imaging and quantification of NO based on fluorescence resonance energy transfer-photoinduced electron transfer (FRET-PET). In this developed probe, coumarin (CM) and naphthalimide with o-phenylenediamine (NPM) were rationally designed as a fluorescent donor and acceptor, respectively, to enable a ratiometric fluorescence response to NO. The developed NO probe demonstrated good detection linearity with the concentration of NO in the range of 0.100–200 μM, with a detection limit of 19.5 ± 1.00 nM. Considering the advantages of high selectivity, good accuracy and rapid dynamic response (<15 s), the developed NO probe was successfully applied for real-time imaging and accurate quantification of NO in neural stem cells (NSCs) and different regions of mouse brain tissue with a penetration depth of 350 μm. Using this powerful tool, it was found that NO regulated the activation and differentiation of quiescent NSCs (qNSCs). In addition, NO-induced differentiation of qNSCs into neurons was found to be dose-dependent: 50.0 μM NO caused about 50.0% of qNSCs to differentiate into neurons. Moreover, different regions of the mouse brain were observed to be closely related to the concentration of NO, and the concentration of NO in the DG region was found to be lower than that in the S1BF, CA1, LD and CPu of the Alzheimer's disease (AD) mouse brain. The symptoms of AD mice were significantly improved through the treatment with NO-activated NSCs in the DG region.

Insulin dysregulation as a prominent driver of cell cycle re-entry in Alzheimer's disease.

Cell Cycle Re-entry (CCR) is observed in several neurological disorders and contributes to cognitive impairment in the early stages. The CCR markers were monitored and correlated functionally with upregulation of Insulin Receptor (INSR) and Insulin like Growth factor 1 Receptor (IGF1R) in Alzheimer's Disease (AD) cell model and mouse brain tissue. The AD cell model was developed as per Majumder et al. (2019) and checked for Cyclin A, D and E Levels after 6 and 11 hours of model development in differentiated SHSY5Y cell line (with 10 µM RA and BDNF for cholinergic neuron like cells) by qPCR. We then checked for expression and activity of INSR and IGF1R in these cells and mouse brain (extracted from FFPE slides) through western blot and qPCR. To assess the correlation of the two events, we exploited overexpression based in-vitro studies for real-time assessment. Levels of INSR and IGF1R both increase on mRNA and protein levels in both cell and animal model. The cyclins A2, D and E however decline when the receptors are overexpressed in a serum free media for 6 hours and 11 hours. The time points were chosen to mimic the average mammalian cell cycle and showed that the upregulation of the receptors negatively impact and reduce cyclin D levels up to 4 fold whereas Cyclin A levels and Cyclin E levels are marginally reduced by 0.48 and 0.5 fold respectively. However, when stimulated with conventional ligands, Insulin and IGF1 or amyloid beta (1-42) the receptors positively correlate with the Cyclin levels. Western blots show that amyloid beta binding phosphorylates the pY1135/1136 of IGF1R, pY1150/1151 of INSR rather than conventional pY1158, 1162 and 1163. The reduction in conventional ligands, Insulin and IGF1 with ageing and build-up of amyloid beta which preferentially phosphorylates a different site could have implications that determines cellular fate after the re-entry. Reference: Majumder, P., Roy, K., Bagh, S. and Mukhopadhyay, D., 2019. Receptor tyrosine kinases (RTKs) consociate in regulatory clusters in Alzheimer's disease and type 2 diabetes. Molecular and cellular biochemistry, 459(1), pp.171-182.

Tailoring Oxygen-Containing Groups on Graphene for Ratiometric Electrochemical Measurements of Ascorbic Acid in Living Subacute Parkinson's Disease Mouse Brains.

Ascorbic acid (AA), a major antioxidant in the central nervous system (CNS), is involved in withstanding oxidative stress that plays a significant role in the pathogenesis of Parkinson's disease (PD). Exploring the AA disturbance in the process of PD is of great value in understanding the molecular mechanism of PD. Herein, by virtue of a carbon fiber electrode (CFE) as a matric electrode, a three-step electrochemical process for tailoring oxygen-containing groups on graphene was well designed: potentiostatic deposition was carried out to fabricate graphene oxide on CFE, electrochemical reduction that assisted in removing the epoxy groups accelerated the electron transfer kinetics of AA oxidation, and electrochemical oxidation that increased the content of the carbonyl group (C═O) generated an inner-reference signal. The mechanism was solidified by ab initio calculations by comparing AA absorption on defected models of graphene functionalized with different oxygen groups including carboxyl, hydroxyl, epoxy, and carbonyl. It was found that epoxy groups would hinder the physical absorption of AA onto graphene, while other functional groups would be beneficial to it. Biocompatible polyethylenedioxythiophene (PEDOT) was further rationally assembled to improve the antifouling property of graphene. As a result, a new platform for ratiometric electrochemical measurements of AA with high sensitivity, excellent selectivity, and reproducibility was established. In vivo determination of AA levels in different regions of living mouse brains by the proposed method demonstrated that AA decreased remarkably in the hippocampus and cortex of a subacute PD mouse than those of a normal mouse.

Sex-specific alterations in NAD+ metabolism in 3xTg Alzheimer's disease mouse brain assessed by quantitative targeted LC-MS.

Levels of nicotinamide adenine dinucleotide (NAD+) are known to decline with age and have been associated with impaired mitochondrial function leading to neurodegeneration, a key facet of Alzheimer's disease (AD). NAD+synthesis is sustained via tryptophan‐kynurenine (Trp‐Kyn) pathway as de novo synthesis route, and salvage pathways dependent on the availability of nicotinic acid and nicotinamide. While being currently investigated as a multifactorial disease with a strong metabolic component, AD remains without curative treatment and important sex differences were reported in relation to disease onset and progression. The aim of this study was to reveal the potential deregulation of NAD+metabolism in AD with the direct analysis of NAD+precursors in the mouse brain tissue (wild type (WT) versus triple transgenic (3xTg) AD), using a sex‐balanced design. To this end, we developed a quantitative liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) method, which allowed for the measurement of the full spectrum of NAD+precursors and intermediates in all three pathways. In brain tissue of mice with developed AD symptoms, a decrease in kynurenine (Kyn) versus increase in kynurenic acid (KA) levels were observed in both sexes with a significantly higher increment of KA in males. These alterations in Trp‐Kyn pathway might be a consequence of neuroinflammation and a compensatory production of neuroprotective kynurenic acid. In the NAD+ salvage pathway, significantly lower levels of nicotinamide mononucleotide (NMN) were measured in the AD brain of males and females. Depletion of NMN implies the deregulation of salvage pathway critical for maintaining optimal NAD+ levels and mitochondrial and neuronal function.

D-Glucose uptake and clearance in the tauopathy Alzheimer’s disease mouse brain detected by on-resonance variable delay multiple pulse MRI

In this study, we applied on-resonance variable delay multiple pulse (onVDMP) MRI to study D-glucose uptake in a mouse model of Alzheimer’s disease (AD) tauopathy and demonstrated its feasibility in discriminating AD mice from wild-type mice. The D-glucose uptake in the cortex of AD mice (1.70 ± 1.33%) was significantly reduced compared to that of wild-type mice (5.42 ± 0.70%, p = 0.0051). Also, a slower D-glucose uptake rate was found in the cerebrospinal fluid (CSF) of AD mice (0.08 ± 0.01 min−1) compared to their wild-type counterpart (0.56 ± 0.1 min−1, p < 0.001), which suggests the presence of an impaired glucose transporter on both blood–brain and blood–CSF barriers of these AD mice. Clearance of D-glucose was observed in the CSF of wild-type mice but not AD mice, which suggests dysfunction of the glymphatic system in the AD mice. The results in this study indicate that onVDMP MRI could be a cost-effective and widely available method for simultaneously evaluating glucose transporter and glymphatic function of AD. This study also suggests that tau protein affects the D-glucose uptake and glymphatic impairment in AD at a time point preceding neurofibrillary tangle pathology.

Huntington's Disease: Genome-wide Neuroprotection Screening Goes Viral

Forward genetic screen, typically performed in invertebrates or mammalian cell lines, has been instrumental in discovering genes essential for neural function. In this issue of Neuron, Wertz etal. (2020) demonstrate the first viral-mediated, genome-wide screen to identify neuroprotective genes in wild-type and Huntington's disease (HD) mouse brains.

An activatable near-infrared fluorescent probe for methylglyoxal imaging in Alzheimer's disease mice

Visual detection of the methylglyoxal (MGO) level in the brain is critical for understanding its role in the onset and progression of AD. Herein, we disclosed a NIR fluorescent probe, DBTPP, for detecting MGO by utilizing a thiadiazole-fused o-phenylenediamine moiety as a MGO-specific sensing unit. DBTPP exhibits a series of distinct advantages, such as NIR emission, high selectivity and sensitivity, excellent acid-stability, and a huge off-on ratio. The probe could accurately monitor both exogenous and endogenous MGO variations in SH-SY5Y cells. Besides, it was able to image the endogenous MGO in a transgenic AD mouse model successfully, suggesting the great potential of MGO as a biomarker for early AD diagnosis.

Global Metabolic Shifts in Age and Alzheimer's Disease Mouse Brains Pivot at NAD+/NADH Redox Sites.

Age and Alzheimer’s disease (AD) share some common features such as cognitive impairments, memory loss, metabolic disturbances, bioenergetic deficits, and inflammation. Yet little is known on how systematic shifts in metabolic networks depend on age and AD. In this work, we investigated the global metabolomic alterations in non-transgenic (NTg) and triple-transgenic (3xTg-AD) mouse brain hippocampus as a function of age by using untargeted Ultrahigh Performance Liquid Chromatography-tandem Mass Spectroscopy (UPLC-MS/MS). We observed common metabolic patterns with aging in both NTg and 3xTg-AD brains involved in energy-generating pathways, fatty acids oxidation, glutamate, and sphingolipid metabolism. We found age-related downregulation of metabolites from reactions in glycolysis that consumed ATP and in the TCA cycle, especially at NAD+/NADH-dependent redox sites, where age- and AD-associated limitations in the free NADH may alter reactions. Conversely, metabolites increased in glycolytic reactions in which ATP is produced. With age, inputs to the TCA cycle were increased including fatty acid β-oxidation and glutamine. Overall age- and AD-related changes were > 2-fold when comparing the declines of upstream metabolites of NAD+/NADH-dependent reactions to the increases of downstream metabolites (p = 10-5, n = 8 redox reactions). Inflammatory metabolites such as ceramides and sphingosine-1-phosphate also increased with age. Age-related decreases in glutamate, GABA, and sphingolipid were seen which worsened with AD genetic load in 3xTg-AD brains, possibly contributing to synaptic, learning- and memory-related deficits. The data support the novel hypothesis that age- and AD-associated metabolic shifts respond to NAD(P)+/NAD(P)H redox-dependent reactions, which may contribute to decreased energetic capacity.

Development of a novel amyloid specific gadolinium contrast agent for MR imaging modality in alzheimer's disease mouse brain

Development of a novel amyloid specific gadolinium contrast agent for MR imaging modality in alzheimer's disease mouse brain