Effects of SPI1-mediated transcriptome remodeling on Alzheimer's disease-related phenotypes in mouse models of Aß amyloidosis.

SPI1 was recently reported as a genetic risk factor for Alzheimer's disease (AD) in large-scale genome-wide association studies. However, it is unknown whether SPI1 should be downregulated or increased to have therapeutic benefits. To investigate the effect of modulating SPI1 levels on AD pathogenesis, we performed extensive biochemical, histological, and transcriptomic analyses using both Spi1-knockdown and Spi1-overexpression mouse models. Here, we show that the knockdown of Spi1 expression significantly exacerbates insoluble amyloid-ß (Aß) levels, amyloid plaque deposition, and gliosis. Conversely, overexpression of Spi1 significantly ameliorates these phenotypes and dystrophic neurites. Further mechanistic studies using targeted and single-cell transcriptomics approaches demonstrate that altered Spi1 expression modulates several pathways, such as immune response pathways and complement system. Our data suggest that transcriptional reprogramming by targeting transcription factors, like Spi1, might hold promise as a therapeutic strategy. This approach could potentially expand the current landscape of druggable targets for AD.

Robust single nucleus RNA sequencing reveals depot-specific cell population dynamics in adipose tissue remodeling during obesity.

Single nucleus RNA sequencing (snRNA-seq), an alternative to single cell RNA sequencing (scRNA-seq), encounters technical challenges in obtaining high-quality nuclei and RNA, persistently hindering its applications. Here, we present a robust technique for isolating nuclei across various tissue types, remarkably enhancing snRNA-seq data quality. Employing this approach, we comprehensively characterize the depot-dependent cellular dynamics of various cell types underlying adipose tissue remodeling during obesity. By integrating bulk nuclear RNA-seq from adipocyte nuclei of different sizes, we identify distinct adipocyte subpopulations categorized by size and functionality. These subpopulations follow two divergent trajectories, adaptive and pathological, with their prevalence varying by depot. Specifically, we identify a key molecular feature of dysfunctional hypertrophic adipocytes, a global shutdown in gene expression, along with elevated stress and inflammatory responses. Furthermore, our differential gene expression analysis reveals distinct contributions of adipocyte subpopulations to the overall pathophysiology of adipose tissue. Our study establishes a robust snRNA-seq method, providing novel insights into the mechanisms orchestrating adipose tissue remodeling during obesity, with broader applicability across diverse biological systems.

AIBP controls TLR4 inflammarafts and mitochondrial dysfunction in a mouse model of Alzheimer's disease.

Microglia-driven neuroinflammation plays an important role in the development of Alzheimer's disease (AD). Microglia activation is accompanied by the formation and chronic maintenance of TLR4 inflammarafts, defined as enlarged and cholesterol-rich lipid rafts serving as an assembly platform for TLR4 dimers and complexes of other inflammatory receptors. The secreted apoA-I binding protein (APOA1BP or AIBP) binds TLR4 and selectively targets cholesterol depletion machinery to TLR4 inflammaraft expressing inflammatory, but not homeostatic microglia. Here we demonstrated that amyloid-beta (Aß) induced formation of TLR4 inflammarafts in microglia in vitro and in the brain of APP/PS1 mice. Mitochondria in Apoa1bp-/- APP/PS1 microglia were hyperbranched and cupped, which was accompanied by increased ROS and the dilated ER. The size and number of Aß plaques and neuronal cell death were significantly increased, and the animal survival was decreased in Apoa1bp-/- APP/PS1 compared to APP/PS1 female mice. These results suggest that AIBP exerts control of TLR4 inflammarafts and mitochondrial dynamics in microglia and plays a protective role in AD associated oxidative stress and neurodegeneration.

APOE loss of function: A genetic shield against Alzheimer's disease.

In this issue of Neuron, Chemparathy et al.1 provide human genetics data suggesting that APOE loss-of-function mutations may confer resistance to Alzheimer's disease (AD) without compromising longevity. These data strongly support the APOE toxic gain-of-function hypothesis for AD.

miRNA family miR-29 inhibits PINK1-PRKN dependent mitophagy via ATG9A.

Loss-of-function mutations in the genes encoding PINK1 and PRKN result in early-onset Parkinson disease (EOPD). Together the encoded enzymes direct a neuroprotective pathway that ensures the elimination of damaged mitochondria via autophagy. We performed a genome-wide high content imaging miRNA screen for inhibitors of the PINK1-PRKN pathway and identified all three members of the miRNA family 29 (miR-29). Using RNAseq we identified target genes and found that siRNA against ATG9A phenocopied the effects of miR-29 and inhibited the initiation of PINK1-PRKN mitophagy. Furthermore, we discovered two rare, potentially deleterious, missense variants (p.R631W and p.S828L) in our EOPD cohort and tested them experimentally in cells. While expression of wild-type ATG9A was able to rescue the effects of miR-29a, the EOPD-associated variants behaved like loss-of-function mutations. Together, our study validates miR-29 and its target gene ATG9A as novel regulators of mitophagy initiation. It further serves as proof-of-concept of finding novel, potentially disease-causing EOPD-linked variants specifically in mitophagy regulating genes. The nomination of genetic variants and biological pathways is important for the stratification and treatment of patients that suffer from devastating diseases, such as EOPD.

Loss of succinyl-CoA synthetase in mouse forebrain results in hypersuccinylation with perturbed neuronal transcription and metabolism.

Lysine succinylation is a subtype of protein acylation associated with metabolic regulation of succinyl-CoA in the tricarboxylic acid cycle. Deficiency of succinyl-CoA synthetase (SCS), the tricarboxylic acid cycle enzyme catalyzing the interconversion of succinyl-CoA to succinate, results in mitochondrial encephalomyopathy in humans. This report presents a conditional forebrain-specific knockout (KO) mouse model of Sucla2, the gene encoding the ATP-specific beta isoform of SCS, resulting in postnatal deficiency of the entire SCS complex. Results demonstrate that accumulation of succinyl-CoA in the absence of SCS leads to hypersuccinylation within the murine cerebral cortex. Specifically, increased succinylation is associated with functionally significant reduced activity of respiratory chain complex I and widescale alterations in chromatin landscape and gene expression. Integrative analysis of the transcriptomic data also reveals perturbations in regulatory networks of neuronal transcription in the KO forebrain. Together, these findings provide evidence that protein succinylation plays a significant role in the pathogenesis of SCS deficiency.

Restoring AIBP expression in the retina provides neuroprotection in glaucoma.

Glaucoma is a neurodegenerative disease manifested in retinal ganglion cell (RGC) death and irreversible blindness. While lowering intraocular pressure (IOP) is the only proven therapeutic strategy in glaucoma, it is insufficient for preventing disease progression, thus justifying the recent focus on targeting retinal neuroinflammation and preserving RGCs. We have identified apolipoprotein A-I binding protein (AIBP) as the protein regulating several mechanisms of retinal neurodegeneration. AIBP controls excessive cholesterol accumulation via upregulating the cholesterol transporter ATP-binding cassette transporter 1 (ABCA1) and reduces inflammatory signaling via toll-like receptor 4 (TLR4) and mitochondrial dysfunction. ABCA1, TLR4 and oxidative phosphorylation components are genetically linked to primary open-angle glaucoma. Here we demonstrated that AIBP and ABCA1 expression was decreased, while TLR4, interleukin 1 beta (IL-1 beta), and the cholesterol content increased in the retina of patients with glaucoma and in mouse models of glaucoma. Restoring AIBP expression by a single intravitreal injection of adeno-associated virus (AAV)-AIBP protected RGCs in glaucomatous DBA/2J mice, in mice with microbead-induced chronic IOP elevation, and optic nerve crush. In addition, AIBP expression attenuated TLR4 and IL-1 beta expression, localization of TLR4 to lipid rafts, reduced cholesterol accumulation, and ameliorated visual dysfunction. These studies collectively indicate that restoring AIBP expression in the glaucomatous retina reduces neuroinflammation and protects RGCs and Muller glia, suggesting the therapeutic potential of AAV-AIBP in human glaucoma.

Feasibility of new patient dose management tool in digital radiography: Using clinical exposure index data of mobile chest radiography in a large university hospital.

The clinical anteroposterior (AP) chest images taken with a mobile radiography system were analyzed in this study to utilize the clinical exposure index (EI) as a patient dose-monitoring tool. The digital imaging and communications in medicine header of 6048 data points exposed under the 90 kVp and 2.5 mAs were extracted using Python for identifying the distribution of clinical EI. Even under the same exposure conditions, the clinical EI distribution was 137.82-4924.38. To determine the cause, the effect of a patient's body shape on EI was confirmed using actual clinical chest AP image data binarized into 0 and 255-pixel values using Python. As a result, the relationship between the direct X-ray area of the chest AP image, the higher the clinical EI, the larger the rate of the direct X-ray area. A conversion equation was also derived to infer entrance surface dose through clinical EI based on the patient thickness. This confirmed the possibility of directly monitoring patient dose through EI without a dosimeter in real-time. Therefore, to use the clinical EI of the mobile radiography system as a patient dose-monitoring tool, the derivation method of clinical EI considers several factors, such as the relationship between patient factors.

Enhanced microglial dynamics and paucity of tau seeding in the amyloid plaque microenvironment contributes to cognitive resilience in Alzheimer's disease.

Asymptomatic Alzheimer's disease (AsymAD) describes the status of subjects with preserved cognition but with identifiable Alzheimer's disease (AD) brain pathology (i.e. Aß-amyloid deposits, neuritic plaques, and neurofibrillary tangles) at autopsy. In this study, we investigated the postmortem brains of a cohort of AsymAD cases to gain insight into the underlying mechanisms of resilience to AD pathology and cognitive decline. Our results showed that AsymAD cases exhibit an enrichment of core plaques and decreased filamentous plaque accumulation, as well as an increase in microglia surrounding this last type. In AsymAD cases we found less pathological tau aggregation in dystrophic neurites compared to AD and tau seeding activity comparable to healthy control subjects. We used spatial transcriptomics to further characterize the plaque niche and found autophagy, endocytosis, and phagocytosis within the top upregulated pathways in the AsymAD plaque niche, but not in AD. Furthermore, we found ARP2, an actin-based motility protein crucial to initiate the formation of new actin filaments, increased within microglia in the proximity of amyloid plaques in AsymAD. Our findings support that the amyloid-plaque microenvironment in AsymAD cases is characterized by microglia with highly efficient actin-based cell motility mechanisms and decreased tau seeding compared to AD. These two mechanisms can potentially provide protection against the toxic cascade initiated by Aß that preserves brain health and slows down the progression of AD pathology.

Network analysis identifies strain-dependent response to tau and tau seeding-associated genes.

Previous research demonstrated that genetic heterogeneity is a critical factor in modeling amyloid accumulation and other Alzheimer's disease phenotypes. However, it is unknown what mechanisms underlie these effects of genetic background on modeling tau aggregate-driven pathogenicity. In this study, we induced tau aggregation in wild-derived mice by expressing MAPT. To investigate the effect of genetic background on the action of tau aggregates, we performed RNA sequencing with brains of C57BL/6J, CAST/EiJ, PWK/PhJ, and WSB/EiJ mice (n = 64) and determined core transcriptional signature conserved in all genetic backgrounds and signature unique to wild-derived backgrounds. By measuring tau seeding activity using the cortex, we identified 19 key genes associated with tau seeding and amyloid response. Interestingly, microglial pathways were strongly associated with tau seeding activity in CAST/EiJ and PWK/PhJ backgrounds. Collectively, our study demonstrates that mouse genetic context affects tau-mediated alteration of transcriptome and tau seeding. The gene modules associated with tau seeding provide an important resource to better model tauopathy.

A simulative deep learning model of SNP interactions on chromosome 19 for predicting Alzheimer's disease risk and rates of disease progression.

BACKGROUND: Identifying genetic patterns that contribute to Alzheimer's disease (AD) is important not only for pre-symptomatic risk assessment but also for building personalized therapeutic strategies. METHODS: We implemented a novel simulative deep learning model to chromosome 19 genetic data from the Alzheimer's Disease Neuroimaging Initiative and the Imaging and Genetic Biomarkers of Alzheimer's Disease datasets. The model quantified the contribution of each single nucleotide polymorphism (SNP) and their epistatic impact on the likelihood of AD using the occlusion method. The top 35 AD-risk SNPs in chromosome 19 were identified, and their ability to predict the rate of AD progression was analyzed. RESULTS: Rs561311966 (APOC1) and rs2229918 (ERCC1/CD3EAP) were recognized as the most powerful factors influencing AD risk. The top 35 chromosome 19 AD-risk SNPs were significant predictors of AD progression. DISCUSSION: The model successfully estimated the contribution of AD-risk SNPs that account for AD progression at the individual level. This can help in building preventive precision medicine.

Endogenous recapitulation of Alzheimer's disease neuropathology through human 3D direct neuronal reprogramming.

Alzheimer's disease (AD) is a neurodegenerative disorder that primarily affects elderly individuals, and is characterized by hallmark neuronal pathologies including extracellular amyloid-ß (Aß) plaque deposition, intracellular tau tangles, and neuronal death. However, recapitulating these age-associated neuronal pathologies in patient-derived neurons has remained a significant challenge, especially for late-onset AD (LOAD), the most common form of the disorder. Here, we applied the high efficiency microRNA-mediated direct neuronal reprogramming of fibroblasts from AD patients to generate cortical neurons in three-dimensional (3D) Matrigel and self-assembled neuronal spheroids. Our findings indicate that neurons and spheroids reprogrammed from both autosomal dominant AD (ADAD) and LOAD patients exhibited AD-like phenotypes linked to neurons, including extracellular Aß deposition, dystrophic neurites with hyperphosphorylated, K63-ubiquitin-positive, seed-competent tau, and spontaneous neuronal death in culture. Moreover, treatment with ß- or γ-secretase inhibitors in LOAD patient-derived neurons and spheroids before Aß deposit formation significantly lowered Aß deposition, as well as tauopathy and neurodegeneration. However, the same treatment after the cells already formed Aß deposits only had a mild effect. Additionally, inhibiting the synthesis of age-associated retrotransposable elements (RTEs) by treating LOAD neurons and spheroids with the reverse transcriptase inhibitor, lamivudine, alleviated AD neuropathology. Overall, our results demonstrate that direct neuronal reprogramming of AD patient fibroblasts in a 3D environment can capture age-related neuropathology and reflect the interplay between Aß accumulation, tau dysregulation, and neuronal death. Moreover, miRNA-based 3D neuronal conversion provides a human-relevant AD model that can be used to identify compounds that can potentially ameliorate AD-associated pathologies and neurodegeneration.

TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo.

The role of TREM2 in Alzheimer's disease (AD) is not fully understood. Previous studies investigating the effect of TREM2 deletion on tauopathy mouse models without the contribution of b-amyloid have focused only on tau overexpression models. Herein, we investigated the effects of TREM2 deficiency on tau spreading using a mouse model in which endogenous tau is seeded to produce AD-like tau features. We found that Trem2-/- mice exhibit attenuated tau pathology in multiple brain regions concomitant with a decreased microglial density. The neuroinflammatory profile in TREM2-deficient mice did not induce an activated inflammatory response to tau pathology. These findings suggest that reduced TREM2 signaling may alter the response of microglia to pathological tau aggregates, impairing their activation and decreasing their capacity to contribute to tau spreading. However, caution should be exercised when targeting TREM2 as a therapeutic entry point for AD until its involvement in tau aggregation and propagation is better understood.

The effect of Abi3 locus deletion on the progression of Alzheimer's disease-related pathologies.

Human genetics studies of Alzheimer's disease (AD) have identified the ABI3 gene as a candidate risk gene for AD. Because ABI3 is highly expressed in microglia, the brain's immune cells, it was suggested that ABI3 might impact AD pathogenesis by regulating the immune response. Recent studies suggest that microglia have multifaceted roles in AD. Their immune response and phagocytosis functions can have beneficial effects in the early stages of AD by clearing up amyloid-beta (Aß) plaques. However, they can be harmful at later stages due to their continuous inflammatory response. Therefore, it is important to understand the role of genes in microglia functions and their impact on AD pathologies along the progression of the disease. To determine the role of ABI3 at the early stage of amyloid pathology, we crossed Abi3 knock-out mice with the 5XFAD Aß-amyloidosis mouse model and aged them until 4.5-month-old. Here, we demonstrate that deletion of the Abi3 locus increased Aß plaque deposition, while there was no significant change in microgliosis and astrogliosis. Transcriptomic analysis indicates alterations in the expression of immune genes, such as Tyrobp, Fcer1g, and C1qa. In addition to the transcriptomic changes, we found elevated cytokine protein levels in Abi3 knock-out mouse brains, strengthening the role of ABI3 in neuroinflammation. These findings suggest that loss of ABI3 function may exacerbate AD progression by increasing Aß accumulation and inflammation starting from earlier stages of the pathology.

Network analysis reveals strain-dependent response to misfolded tau aggregates.

Mouse genetic backgrounds have been shown to modulate amyloid accumulation and propagation of tau aggregates. Previous research into these effects has highlighted the importance of studying the impact of genetic heterogeneity on modeling Alzheimer's disease. However, it is unknown what mechanisms underly these effects of genetic background on modeling Alzheimer's disease, specifically tau aggregate-driven pathogenicity. In this study, we induced tau aggregation in wild-derived mice by expressing MAPT (P301L). To investigate the effect of genetic background on the action of tau aggregates, we performed RNA sequencing with brains of 6-month-old C57BL/6J, CAST/EiJ, PWK/PhJ, and WSB/EiJ mice (n=64). We also measured tau seeding activity in the cortex of these mice. We identified three gene signatures: core transcriptional signature, unique signature for each wild-derived genetic background, and tau seeding-associated signature. Our data suggest that microglial response to tau seeds is elevated in CAST/EiJ and PWK/PhJ mice. Together, our study provides the first evidence that mouse genetic context influences the seeding of tau. SUMMARY: Seeding of tau predates the phosphorylation and spreading of tau aggregates. Acri and colleagues report transcriptomic responses to tau and elevated tau seeds in wild-derived mice. This paper creates a rich resource by combining genetics, tau biosensor assays, and transcriptomics.

Adaptive Discount Factor for Deep Reinforcement Learning in Continuing Tasks with Uncertainty.

Reinforcement learning (RL) trains an agent by maximizing the sum of a discounted reward. Since the discount factor has a critical effect on the learning performance of the RL agent, it is important to choose the discount factor properly. When uncertainties are involved in the training, the learning performance with a constant discount factor can be limited. For the purpose of obtaining acceptable learning performance consistently, this paper proposes an adaptive rule for the discount factor based on the advantage function. Additionally, how to use the advantage function in both on-policy and off-policy algorithms is presented. To demonstrate the performance of the proposed adaptive rule, it is applied to PPO (Proximal Policy Optimization) for Tetris in order to validate the on-policy case, and to SAC (Soft Actor-Critic) for the motion planning of a robot manipulator to validate the off-policy case. In both cases, the proposed method results in a better or similar performance compared with cases using the best constant discount factors found by exhaustive search. Hence, the proposed adaptive discount factor automatically finds a discount factor that leads to comparable training performance, and that can be applied to representative deep reinforcement learning problems.

Updated National Diagnostic Reference Levels and Achievable Doses for CT Protocols: A National Survey of Korean Hospitals.

Background: In 2021, the Korean government proposed a new CT diagnostic reference level. This study performed a nationwide survey and developed new DRLs and AD for 13 common CT examinations. We compared other countries' DRLs for CT examinations. Methods: This study investigated the CTDIvol and DLP of the 12 types of CT protocols for adults and brain CT protocol for pediatrics. A total of 7829 CT examinations were performed using 225 scanners. We defined the DRLs values in the distribution of radiation exposure levels to determine the nationwide patient dose and distribution status of the dose. Results: This study showed that the new Korean national CT DRLs are slightly higher or similar to those of previous surveys and are similar or lower than those of other countries. In some protocols, although the DLP value increased, the CTDIvol decreased; therefore, it can be concluded that the patient's dose in CT examinations was well managed. Conclusions: The new CT DRLs were slightly higher than or similar to that of the previous survey and were evaluated to be similar or lower than CT DRLs of other countries. These DRLs will be used for radiation optimization and effective dose calculation for an individual.

Development of an Auxiliary Device for Patellar and Femoral Joint Tangential Axial Radiographic Imaging and a Method for Obtaining an Optimal Radiographic Image Using the Development.

This study evaluated the accuracy of tangential axial radiography of the patellar and femoral joint using an auxiliary device based on three image evaluation criteria, which we named the patellofemoral joint radiography auxiliary device (PJR). To compare the PJR method with conventional radiographic methods, such as Laurin, Merchant, and Settegast, a whole-body phantom (PBU-31) was used and three image evaluation items were set. The radiographic method, the smallest inclination of the patellar and showed the best half lateral image of the patella, is Settegast, and the measurement is 9.40. The second-best PJR measurement is 9.97, and the difference between the two measures is 5.76% (p = 0.001). The radiographic method showing the image with the largest distance between the patellar and femoral joint space is PJR which a measurement is 12.35. The second best Merchant measure is 10.55, and the difference between the two measures is 14.54% (p = 0.001). The method in which the two bones were well overlapped (i.e., evaluate the distortion of the image by measured as the distance between the femoral trochlear groove and the tibial tuberosity) is the PJR and the measurement is -0.37. The second-best Merchant measure is 3.93, and the difference between the two measures is 91.4% (p = 0.001). The Settegast has the image with the smallest inclination of the patella, but the PJR has the image that best describes the patellar-femoral joint and the least distortion of the image. As a result of the comprehensive evaluation, when using PJR, bending the knee by 40° and setting a 140° angle between the long axis of the femur and the long axis of the lower leg were considered to be the most beneficial conditions. Therefore, we propose the use of PJR for tangential axial radiography of the patellar-femoral joint.

Monitoring clinical exposure index and deviation index for dose optimization based on national diagnostic reference level: Focusing on general radiography of extremities.

BACKGROUND: The International Electrotechnical Commission established the concept of the exposure index (EI), target exposure index (EIT) and deviation index (DI). Some studies have conducted to utilize the EI as a patient dose monitoring tool in the digital radiography (DR) system. OBJECTIVE: To establish the appropriate clinical EIT, this study aims to introduce the diagnostic reference level (DRL) for general radiography and confirm the usefulness of clinical EI and DI. METHODS: The relationship between entrance surface dose (ESD) and clinical EI is obtained by exposure under the national radiography conditions of Korea for 7 extremity examinations. The EI value when the ESD is the DRL is set as the clinical EIT, and the change of DI is then checked. RESULTS: The clinical EI has proportional relationship with ESD and is affected by the beam quality. When the clinical EIT is not adjusted according to the revision of DRLs, there is a difference of up to 2.03 in the DI value and may cause an evaluation error of up to 1.6 times for patient dose. CONCLUSIONS: If the clinical EIT is periodically managed according to the environment of medical institution, the appropriate patient dose and image exposure can be managed based on the clinical EI, EIT, and DI.

Deletion of the Alzheimer's disease risk gene Abi3 locus results in obesity and systemic metabolic disruption in mice.

Alzheimer's disease (AD) genetics studies have identified a coding variant within ABI3 gene that increases the risk of developing AD. Recently, we demonstrated that deletion of the Abi3 gene locus dramatically exacerbates AD neuropathology in a transgenic mouse model of amyloidosis. In the course of this AD project, we unexpectedly found that deletion of the Abi3 gene locus resulted in a dramatic obese phenotype in non-transgenic mice. Here, we report our investigation into this serendipitous metabolic finding. Specifically, we demonstrate that mice with deletion of the Abi3 gene locus (Abi3-/- ) have dramatically increased body weight and body fat. Further, we determined that Abi3-/- mice have impaired energy expenditure. Additionally, we found that deletion of the Abi3 gene locus altered gene expression within the hypothalamus, particularly within immune-related pathways. Subsequent immunohistological analysis of the central nervous system (CNS) revealed that microglia number and area were decreased specifically within the mediobasal hypothalamus of Abi3-/- mice. Altogether, this investigation establishes the functional importance of the Abi3 gene locus in the regulation of systemic metabolism and maintenance of healthy body weight. While our previous findings indicated the importance of Abi3 in neurodegeneration, this study indicates that Abi3 related functions are also essential for metabolic regulation.