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

Asymptomatic Alzheimer's disease (AsymAD) describes the status of individuals with preserved cognition but identifiable Alzheimer's disease (AD) brain pathology (i.e., beta-amyloid (Aß) deposits, neuritic plaques, and neurofibrillary tangles) at autopsy. In this study, we investigated the postmortem brains of a cohort of AsymAD subjects to gain insight into the mechanisms underlying resilience to AD pathology and cognitive decline. Our results showed that AsymAD cases exhibit enrichment in core plaques, decreased filamentous plaque accumulation, and increased plaque-surrounding microglia. Less pathological tau aggregation in dystrophic neurites was found in AsymAD brains than in AD brains, and tau seeding activity was comparable to that in healthy brains. We used spatial transcriptomics to characterize the plaque niche further and revealed autophagy, endocytosis, and phagocytosis as the pathways associated with the genes upregulated in the AsymAD plaque niche. Furthermore, the levels of ARP2 and CAP1, which are actin-based motility proteins that participate in the dynamics of actin filaments to allow cell motility, were increased in the microglia surrounding amyloid plaques in AsymAD cases. Our findings suggest that the amyloid-plaque microenvironment in AsymAD cases is characterized by the presence of microglia with highly efficient actin-based cell motility mechanisms and decreased tau seeding compared with that in AD brains. These two mechanisms can potentially protect against the toxic cascade initiated by Aß, preserving brain health, and slowing AD pathology progression.

Da Vinci vs. Hugo RAS for robot-assisted radical prostatectomy: a prospective comparative single-center study.

PURPOSE: To evaluate Hugo RAS against the Da Vinci system for Robot-Assisted Radical Prostatectomy (RARP) in prostate cancer treatment. METHODS: We compared outcomes of 150 patients with prostate cancer undergoing RARP with either Hugo or Da Vinci systems. Our analysis included operative, postoperative, pathological, and functional outcomes. RESULTS: Both groups had 75 patients. Baseline characteristics and tumor features were similar. Intraoperatively, Da Vinci had a shorter docking time (10.45 vs. 18.62 min, p = 0.02), but total operative times were comparable (145.34 vs 138.95, p = 0.85). Hugo outperformed in neck dissection and lymphadenectomy times (22 vs 13.67 min, p = 0.027 and 37.82 vs 45.77 min, p = 0.025). Postoperative metrics like stay duration, catheter time, and complications showed no significant difference. Functional results, using IPSS and IIEF5, were similar between systems. Six Da Vinci patients (8%) and nine Hugo patients (12%) experienced social incontinence (p = 0.072). Pathological outcomes like T stage, Gleason Score, and nodes removed were alike. However, Hugo had more positive surgical margins (20% vs. 10.67%, p = 0.034). CONCLUSIONS: RARP outcomes using Hugo RAS were similar to the Da Vinci system in our study. More research and extended follow-up are required to ascertain long-term oncological and functional results.

Loss of TDP-43 splicing repression occurs early in the aging population and is associated with Alzheimer's disease neuropathologic changes and cognitive decline.

LATE-NC, the neuropathologic changes of limbic-predominant age-related TAR DNA-binding protein 43 kDa (TDP-43) encephalopathy are frequently associated with Alzheimer's disease (AD) and cognitive impairment in older adults. The association of TDP-43 proteinopathy with AD neuropathologic changes (ADNC) and its impact on specific cognitive domains are not fully understood and whether loss of TDP-43 function occurs early in the aging brain remains unknown. Here, using a large set of autopsies from the Baltimore Longitudinal Study of Aging (BLSA) and another younger cohort, we were able to study brains from subjects 21-109 years of age. Examination of these brains show that loss of TDP-43 splicing repression, as judged by TDP-43 nuclear clearance and expression of a cryptic exon in HDGFL2, first occurs during the 6th decade, preceding by a decade the appearance of TDP-43+ neuronal cytoplasmic inclusions (NCIs). We corroborated this observation using a monoclonal antibody to demonstrate a cryptic exon-encoded neoepitope within HDGFL2 in neurons exhibiting nuclear clearance of TDP-43. TDP-43 nuclear clearance is associated with increased burden of tau pathology. Age at death, female sex, high CERAD neuritic plaque score, and high Braak neurofibrillary stage significantly increase the odds of LATE-NC. Faster rates of cognitive decline on verbal memory (California Verbal Learning Test immediate recall), visuospatial ability (Card Rotations Test), mental status (MMSE) and semantic fluency (Category Fluency Test) were associated with LATE-NC. Notably, the effects of LATE-NC on verbal memory and visuospatial ability are independent of ADNC. However, the effects of TDP-43 nuclear clearance in absence of NCI on the longitudinal trajectories and levels of cognitive measures are not significant. These results establish that loss of TDP-43 splicing repression is an early event occurring in the aging population during the development of TDP-43 proteinopathy and is associated with increased tau pathology. Furthermore, LATE-NC correlates with high levels of ADNC but also has an impact on specific memory and visuospatial functions in aging that is independent of AD.

Organ-Sparing Surgery for Testicular Germ Cell Tumors: A Current Perspective.

Background and Objectives: We aimed to evaluate the oncological and functional outcomes of organ-sparing surgery for testicular germ cell tumors, a procedure that seeks to strike a balance between effective cancer control and organ preservation, in the treatment of testicular tumors. We aimed to discuss the surgical technique and complications, and determine the appropriate candidate selection for this approach. Material and Methods: A comprehensive literature search was conducted to identify relevant studies on organ-sparing surgery for testicular tumors. Various databases, including PubMed, Embase, and Cochrane Library, were used. Studies reporting on surgical techniques, complications, and oncologic and functional outcomes were included for analysis. Results: Current evidence suggests that organ-sparing surgery for testicular germ cell tumors can be considered a safe and efficacious alternative to radical orchiectomy. The procedure is associated with adequate oncological control, as indicated by low recurrence rates and low complication rates. Endocrine testicular function can be preserved in around 80-90% of patients and paternity can be achieved in approximately half of the patients. Candidate selection for this surgery is typically based on the following criteria: pre-surgery normal levels of testosterone and luteinizing hormone, synchronous or metachronous bilateral tumors, tumor in a solitary testis, and tumor size less than 50% of the testis. Conclusions: Organ-sparing surgery for testicular germ cell tumors offers a promising approach that balances oncological control and preservation of testicular function. Further research, including large-scale prospective studies and long-term follow-ups, is warranted to validate the effectiveness and durability of organ-sparing surgery and to identify optimal patient selection criteria.

Methodological design for the macro-location of a micropollutants monitoring network in tropical rivers: a case study in Cauca River.

Establishing scientifically the macro-location of a micropollutants monitoring network in tropical Andean rivers is a complex process, because information gathering is restricted by high-cost of analysis and limited availability of analytical techniques, which lead to inadequate sampling strategies that hinder the representativeness of samples. Thus, this work proposes a methodology for determining the number of representative sampling sections in a micropollutant monitoring network to characterise the ecological risk in tropical Andean torrential rivers. The proposed methodology consists of four stages: identification of the potential sampling units by Spline interpolation; calculation of the number of representative sections for a stratified sampling with an acceptable level of confidence and error; spatial allocation of the potential sampling units into sections by hierarchical cluster analysis; and representation of the spatial distribution of the sampling sections through a geographic information system (GIS). The proposed methodology is dynamic, and therefore, it can be revisited as more data are obtained in the subsequent years; it has the possibility of being applied to other inter-Andean valley rivers that interact with the tropical Andean sloppy mountains and serves as a tool for decision making by environmental authorities regarding the optimisation of the existing monitoring networks in terms of micropollutants to promote sustainable management of water resources. The proposed methodology is applied in the Upper Cauca River Basin (UCRB), which is located in southwest Colombia, South America.

Ancient DNA from the extinct South American giant glyptodont Doedicurus sp. (Xenarthra: Glyptodontidae) reveals that glyptodonts evolved from Eocene armadillos.

Glyptodonts were giant (some of them up to ~2400 kg), heavily armoured relatives of living armadillos, which became extinct during the Late Pleistocene/early Holocene alongside much of the South American megafauna. Although glyptodonts were an important component of Cenozoic South American faunas, their early evolution and phylogenetic affinities within the order Cingulata (armoured New World placental mammals) remain controversial. In this study, we used hybridization enrichment and high-throughput sequencing to obtain a partial mitochondrial genome from Doedicurus sp., the largest (1.5 m tall, and 4 m long) and one of the last surviving glyptodonts. Our molecular phylogenetic analyses revealed that glyptodonts fall within the diversity of living armadillos. Reanalysis of morphological data using a molecular 'backbone constraint' revealed several morphological characters that supported a close relationship between glyptodonts and the tiny extant fairy armadillos (Chlamyphorinae). This is surprising as these taxa are among the most derived cingulates: glyptodonts were generally large-bodied and heavily armoured, while the fairy armadillos are tiny (~9-17 cm) and adapted for burrowing. Calibration of our phylogeny with the first appearance of glyptodonts in the Eocene resulted in a more precise timeline for xenarthran evolution. The osteological novelties of glyptodonts and their specialization for grazing appear to have evolved rapidly during the Late Eocene to Early Miocene, coincident with global temperature decreases and a shift from wet closed forest towards drier open woodland and grassland across much of South America. This environmental change may have driven the evolution of glyptodonts, culminating in the bizarre giant forms of the Pleistocene.

Fat embolism syndrome associated with atraumatic compartment syndrome of the bilateral upper extremities: An unreported etiology.

Fat embolism syndrome (FES) is a potentially life-threatening condition that develops when fat embolism leads to clinical symptoms and multisystem dysfunction. The classic triad of respiratory distress, neurologic symptoms, and petechial rash are non-specific, and the lack of specific laboratory tests makes the diagnosis of FES difficult. Although FES is most common after long bone fractures, multiple conditions some of which are atraumatic have been associated with the development of FES. We report a case of FES that occurred in the setting of a non-traumatic compartment syndrome of the upper extremities. The pathologic and clinical findings, pathophysiology, diagnostic challenges, and pathologic methods to properly diagnose FES are discussed with a review of the relevant literature. This case highlights the importance of the autopsy in making a diagnosis of FES in cases where death could otherwise be incorrectly attributed to multi-organ system failure, shock, or sepsis.

Da Vinci and Hugo RAS Platforms for robot-assisted partial nephrectomy: a preliminary prospective comparative analysis of the outcomes.

BACKGROUND: Robot-assisted partial nephrectomy (RAPN) has emerged as the preferred approach for T1 renal-cell-carcinoma. As new robotic platforms like Hugo RAS emerge, we seek to understand their potential in achieving similar RAPN outcomes as the established Da Vinci system. METHODS: A prospective single-center comparative study was conducted, and 50 patients selected for RAPN were enrolled (25 Da Vinci Xi; 25 Hugo RAS). The choice of robotic system was based solely on hospital logistics criteria. Surgeries were performed by expert surgeons. Demographic data, tumor characteristics, operative details and postoperative outcomes were collected. SPSS version 22.0 was used for statistical analyses. RESULTS: The average age of patients was 62.52±9.47 years, with no significant differences in median age, sex, and nephrometry scores between groups. Da Vinci group showed a significantly shorter docking time (12.56 vs. 20.08 min; P<0.01), while other intraoperative measures like console time and warm ischemia time were similar. The Hugo RAS group had a shorter renorraphy time (14.33 vs. 18.84 min; P=0.024). Postoperative outcomes and surgical margin positivity showed no significant differences. Each group had one patient (4%) who developed major surgical complications (Clavien IIIa). Trifecta rates were comparable between both groups (Da Vinci 88% vs. Hugo RAS 84%; P=0.93). CONCLUSIONS: Initial findings suggest similar perioperative outcomes for RAPN when using Hugo RAS compared to the Da Vinci system. Further research with long-term follow-up is necessary to evaluate oncological and functional outcomes.

The autophagy adaptor TRIAD3A promotes tau fibrillation by nested phase separation.

Multiple neurodegenerative diseases are characterized by aberrant proteinaceous accumulations of tau. Here, we report a RING-in-between-RING-type E3 ligase, TRIAD3A, that functions as an autophagy adaptor for tau. TRIAD3A(RNF216) is an essential gene with mutations causing age-progressive neurodegeneration. Our studies reveal that TRIAD3A E3 ligase catalyses mixed K11/K63 polyubiquitin chains and self-assembles into liquid-liquid phase separated (LLPS) droplets. Tau is ubiquitinated and accumulates within TRIAD3A LLPS droplets and, via LC3 interacting regions, targets tau for autophagic degradation. Unexpectedly, tau sequestered within TRIAD3A droplets rapidly converts to fibrillar aggregates without the transitional liquid phase of tau. In vivo studies show that TRIAD3A decreases the accumulation of phosphorylated tau in a tauopathy mouse model, and a disease-associated mutation of TRIAD3A increases accumulation of phosphorylated tau, exacerbates gliosis and increases pathological tau spreading. In human Alzheimer disease brain, TRIAD3A co-localizes with tau amyloid in multiple histological forms, suggesting a role in tau proteostasis. TRIAD3A is an autophagic adaptor that utilizes E3 ligase and LLPS as a mechanism to capture cargo and appears especially relevant to neurodegenerative diseases.

Disruption of nuclear speckle integrity dysregulates RNA splicing in C9ORF72-FTD/ALS.

Expansion of an intronic (GGGGCC)n repeat within the C9ORF72 gene is the most common genetic cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (C9-FTD/ALS), characterized with aberrant repeat RNA foci and noncanonical translation-produced dipeptide repeat (DPR) protein inclusions. Here, we elucidate that the (GGGGCC)n repeat RNA co-localizes with nuclear speckles and alters their phase separation properties and granule dynamics. Moreover, the essential nuclear speckle scaffold protein SRRM2 is sequestered into the poly-GR cytoplasmic inclusions in the C9-FTD/ALS mouse model and patient postmortem tissues, exacerbating the nuclear speckle dysfunction. Impaired nuclear speckle integrity induces global exon skipping and intron retention in human iPSC-derived neurons and causes neuronal toxicity. Similar alternative splicing changes can be found in C9-FTD/ALS patient postmortem tissues. This work identified novel molecular mechanisms of global RNA splicing defects caused by impaired nuclear speckle function in C9-FTD/ALS and revealed novel potential biomarkers or therapeutic targets.

Exploring [11C]CPPC as a CSF1R-targeted PET Imaging Marker for Early Parkinson's Disease Severity.

Neuroinflammation through enhanced innate immunity is thought play a role in the pathogenesis of Parkinson's disease (PD). Methods for monitoring neuroinflammation in living patients with PD are currently limited to positron emission tomography (PET) ligands that lack specificity in labeling immune cells in the nervous system. The colony stimulating factor 1 receptor (CSF1R) plays a crucial role in microglial function, an important cellular contributor to the nervous system's innate immune response. Using immunologic methods, we show that CSF1R in human brain is colocalized with the microglial marker, ionized calcium binding adaptor molecule 1 (Iba1). In PD, CSF1R immunoreactivity is significantly increased in PD across multiple brain regions, with the largest differences in the midbrain versus controls. Autoradiography revealed significantly increased [3H]JHU11761 binding in the inferior parietal cortex of PD patients. PET imaging demonstrated that higher [11C]CPPC binding in the striatum was associated with greater motor disability in PD. Furthermore, increased [11C]CPPC binding in various regions correlated with more severe motor disability and poorer verbal fluency. This study finds that CSF1R expression is elevated in PD and that [11C]CPPC-PET imaging of CSF1R is indicative of motor and cognitive impairments in the early stages of the disease. Moreover, the study underscores the significance of CSF1R as a promising biomarker for neuroinflammation in Parkinson's disease, suggesting its potential use for non-invasive assessment of disease progression and severity, leading to earlier diagnosis and targeted interventions.

Lymphocyte-Activation Gene 3 Facilitates Pathological Tau Neuron-to-Neuron Transmission.

The spread of prion-like protein aggregates is a common driver of pathogenesis in various neurodegenerative diseases, including Alzheimer's disease (AD) and related Tauopathies. Tau pathologies exhibit a clear progressive spreading pattern that correlates with disease severity. Clinical observation combined with complementary experimental studies has shown that Tau preformed fibrils (PFF) are prion-like seeds that propagate pathology by entering cells and templating misfolding and aggregation of endogenous Tau. While several cell surface receptors of Tau are known, they are not specific to the fibrillar form of Tau. Moreover, the underlying cellular mechanisms of Tau PFF spreading remain poorly understood. Here, it is shown that the lymphocyte-activation gene 3 (Lag3) is a cell surface receptor that binds to PFF but not the monomer of Tau. Deletion of Lag3 or inhibition of Lag3 in primary cortical neurons significantly reduces the internalization of Tau PFF and subsequent Tau propagation and neuron-to-neuron transmission. Propagation of Tau pathology and behavioral deficits induced by injection of Tau PFF in the hippocampus and overlying cortex are attenuated in mice lacking Lag3 selectively in neurons. These results identify neuronal Lag3 as a receptor of pathologic Tau in the brain，and for AD and related Tauopathies, a therapeutic target.

MAPT H2 haplotype and risk of Pick's disease in the Pick's disease International Consortium: a genetic association study.

BACKGROUND: Pick's disease is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. Pick's disease is pathologically defined by the presence in the frontal and temporal lobes of Pick bodies, composed of hyperphosphorylated, three-repeat tau protein, encoded by the MAPT gene. MAPT has two distinct haplotypes, H1 and H2; the MAPT H1 haplotype is the major genetic risk factor for four-repeat tauopathies (eg, progressive supranuclear palsy and corticobasal degeneration), and the MAPT H2 haplotype is protective for these disorders. The primary aim of this study was to evaluate the association of MAPT H2 with Pick's disease risk, age at onset, and disease duration. METHODS: In this genetic association study, we used data from the Pick's disease International Consortium, which we established to enable collection of data from individuals with pathologically confirmed Pick's disease worldwide. For this analysis, we collected brain samples from individuals with pathologically confirmed Pick's disease from 35 sites (brainbanks and hospitals) in North America, Europe, and Australia between Jan 1, 2020, and Jan 31, 2023. Neurologically healthy controls were recruited from the Mayo Clinic (FL, USA, or MN, USA between March 1, 1998, and Sept 1, 2019). For the primary analysis, individuals were directly genotyped for the MAPT H1-H2 haplotype-defining variant rs8070723. In a secondary analysis, we genotyped and constructed the six-variant-defined (rs1467967-rs242557-rs3785883-rs2471738-rs8070723-rs7521) MAPT H1 subhaplotypes. Associations of MAPT variants and MAPT haplotypes with Pick's disease risk, age at onset, and disease duration were examined using logistic and linear regression models; odds ratios (ORs) and ß coefficients were estimated and correspond to each additional minor allele or each additional copy of the given haplotype. FINDINGS: We obtained brain samples from 338 people with pathologically confirmed Pick's disease (205 [61%] male and 133 [39%] female; 338 [100%] White) and 1312 neurologically healthy controls (611 [47%] male and 701 [53%] female; 1312 [100%] White). The MAPT H2 haplotype was associated with increased risk of Pick's disease compared with the H1 haplotype (OR 1·35 [95% CI 1·12 to 1·64], p=0·0021). MAPT H2 was not associated with age at onset (ß -0·54 [95% CI -1·94 to 0·87], p=0·45) or disease duration (ß 0·05 [-0·06 to 0·16], p=0·35). Although not significant after correcting for multiple testing, associations were observed at p less than 0·05: with risk of Pick's disease for the H1f subhaplotype (OR 0·11 [0·01 to 0·99], p=0·049); with age at onset for H1b (ß 2·66 [0·63 to 4·70], p=0·011), H1i (ß -3·66 [-6·83 to -0·48], p=0·025), and H1u (ß -5·25 [-10·42 to -0·07], p=0·048); and with disease duration for H1x (ß -0·57 [-1·07 to -0·07], p=0·026). INTERPRETATION: The Pick's disease International Consortium provides an opportunity to do large studies to enhance our understanding of the pathobiology of Pick's disease. This study shows that, in contrast to the decreased risk of four-repeat tauopathies, the MAPT H2 haplotype is associated with an increased risk of Pick's disease in people of European ancestry. This finding could inform development of isoform-related therapeutics for tauopathies. FUNDING: Wellcome Trust, Rotha Abraham Trust, Brain Research UK, the Dolby Fund, Dementia Research Institute (Medical Research Council), US National Institutes of Health, and the Mayo Clinic Foundation.

Isotope geochemistry as a natural tag of fish in Patagonian freshwater environments: The invasive Chinook salmon case.

Patagonian aquatic environments have been invaded since the end of the last century by different species of salmonids. Knowing the natal origin and homing/straying rate of the salmonids in colonised environments is essential to understanding the dispersal mechanisms and developing management plans. In the last two decades, Chinook salmon Oncorhynchus tshawytscha showed the greatest natural dispersal capacity in Patagonia. The main goal of this study was to evaluate the environmental strontium isotope ratio (87Sr/86Sr) as a potential natural tag to infer the natal origin and ontogenetic habitat use of salmonids in Patagonia, specifically Chinook salmon. 87Sr/86Sr ratio was determined in water samples from 26 sites distributed in 14 Atlantic and Pacific basins in low and high water seasons. Environmental 87Sr/86Sr showed greater spatial than temporal variation, revealing great potential as a tool to infer the natal origin and life history of several migratory fish species in Patagonia. Otolith core-to-edge 87Sr/86Sr profiles were also analysed in 108 Chinook salmon from six basins. A cluster analysis based on the Unweighted Pair Group method (UPGMA) and Euclidean distances without prior classification grouped the sampled rivers into five main groups with significantly different (p < 0.05) isotopic ratios, sometimes integrated basins with different slopes (Atlantic or Pacific). The cluster analysis based on the natal 87Sr/86Sr period in otolith (∼natal origin) showed clear segregation between the Atlantic and Pacific samples. A mismatch between water and otolith natal 87Sr/86Sr ratio was detected in some Atlantic basins (e.g. De las Vueltas River in Santa Cruz Basin) and Pacific (e.g. Liquiñe Basin) and, which could be explained either by straying behaviours or by large geochemical variability between tributaries, within river systems. Our results showed that 87Sr/86Sr is a useful natural tag to trace the life history of migratory fishes in Patagonia, especially for invasive species such as Chinook salmon.

Hippocampal synaptic alterations associated with tau pathology in primary age-related tauopathy.

Primary age-related tauopathy (PART) is characterized by aggregation of tau in the mesial temporal lobe in older individuals. High pathologic tau stage (Braak stage) or a high burden of hippocampal tau pathology has been associated with cognitive impairment in PART. However, the potential underlying mechanisms are not well understood. Cognitive impairment in many neurodegenerative diseases correlates with synaptic loss, raising the question of whether synaptic loss also occurs in PART. To address this, we investigated synaptic changes associated with tau Braak stage and high tau pathology burden in PART using synaptophysin and phospho-tau immunofluorescence. We compared 12 cases of definite PART with 6 controls and 6 Alzheimer disease cases. In this study, the hippocampal CA2 region showed loss of synaptophysin puncta and intensity in cases of PART with either a high stage (Braak IV) or a high burden of neuritic tau pathology. There was also loss of synaptophysin intensity in CA3 associated with a high stage or high burden of tau pathology. Loss of synaptophysin was present in Alzheimer disease, but the pattern appeared distinct. These novel findings suggest the presence of synaptic loss associated with either a high hippocampal tau burden or a Braak stage IV in PART.

Hippocampal Synaptic Alterations Associated with Tau Pathology in Primary Age-Related Tauopathy.

Primary Age-Related Tauopathy (PART) is characterized by the aggregation of tau in the mesial temporal lobe in older individuals. High pathologic tau stage (Braak stage) or a high burden of hippocampal tau pathology have been associated with cognitive impairment in PART. However, the underlying mechanisms of cognitive impairment in PART are not well understood. Cognitive impairment in many neurodegenerative diseases correlates with synaptic loss, raising the question of whether synaptic loss occurs in PART. To address this, we investigated synaptic changes associated with tau Braak stage and a high tau pathology burden in PART using synaptophysin and phospho-tau immunofluorescence. We compared twelve cases of definite PART with six young controls and six Alzheimer's disease cases. In this study, we identified loss of synaptophysin puncta and intensity in the CA2 region of the hippocampus in cases of PART with either a high stage (Braak IV) or a high burden of neuritic tau pathology. There was also loss of synaptophysin intensity in CA3 associated with a high stage or high burden of tau pathology. Loss of synaptophysin signal was present in AD, but the pattern was distinct from that seen in PART. These novel findings suggest the presence of synaptic loss in PART associated with either a high hippocampal tau burden or a Braak stage IV. These synaptic changes raise the possibility that synaptic loss in PART could contribute to cognitive impairment, though future studies including cognitive assessments are needed to address this question.

NMDA Receptor-Arc Signaling Is Required for Memory Updating and Is Disrupted in Alzheimer's Disease.

BACKGROUND: Memory deficits are central to many neuropsychiatric diseases. During acquisition of new information, memories can become vulnerable to interference, yet mechanisms that underlie interference are unknown. METHODS: We describe a novel transduction pathway that links the NMDA receptor (NMDAR) to AKT signaling via the immediate early gene Arc and evaluate its role in memory. The signaling pathway is validated using biochemical tools and transgenic mice, and function is evaluated in assays of synaptic plasticity and behavior. The translational relevance is evaluated in human postmortem brain. RESULTS: Arc is dynamically phosphorylated by CaMKII (calcium/calmodulin-dependent protein kinase II) and binds the NMDAR subunits NR2A/NR2B and a previously unstudied PI3K (phosphoinositide 3-kinase) adapter p55PIK (PIK3R3) in vivo in response to novelty or tetanic stimulation in acute slices. NMDAR-Arc-p55PIK recruits p110α PI3K and mTORC2 (mechanistic target of rapamycin complex 2) to activate AKT. NMDAR-Arc-p55PIK-PI3K-mTORC2-AKT assembly occurs within minutes of exploratory behavior and localizes to sparse synapses throughout hippocampal and cortical regions. Studies using conditional (Nestin-Cre) p55PIK deletion mice indicate that NMDAR-Arc-p55PIK-PI3K-mTORC2-AKT functions to inhibit GSK3 and mediates input-specific metaplasticity that protects potentiated synapses from subsequent depotentiation. p55PIK conditional knockout mice perform normally in multiple behaviors including working memory and long-term memory tasks but exhibit deficits indicative of increased vulnerability to interference in both short-term and long-term paradigms. The NMDAR-AKT transduction complex is reduced in postmortem brain of individuals with early Alzheimer's disease. CONCLUSIONS: A novel function of Arc mediates synapse-specific NMDAR-AKT signaling and metaplasticity that contributes to memory updating and is disrupted in human cognitive disease.

Small RNA Profiles of Brain Tissue-Derived Extracellular Vesicles in Alzheimer's Disease.

BACKGROUND: Extracellular vesicles (EVs) and non-coding RNAs (ncRNAs) are emerging contributors to Alzheimer's disease (AD) pathophysiology. Differential abundance of ncRNAs carried by EVs may provide valuable insights into underlying disease mechanisms. Brain tissue-derived EVs (bdEVs) are particularly relevant, as they may offer valuable insights about the tissue of origin. However, there is limited research on diverse ncRNA species in bdEVs in AD. OBJECTIVE: This study explored whether the non-coding RNA composition of EVs isolated from post-mortem brain tissue is related to AD pathogenesis. METHODS: bdEVs from age-matched late-stage AD patients (n = 23) and controls (n = 10) that had been separated and characterized in our previous study were used for RNA extraction, small RNA sequencing, and qPCR verification. RESULTS: Significant differences of non-coding RNAs between AD and controls were found, especially for miRNAs and tRNAs. AD pathology-related miRNA and tRNA differences of bdEVs partially matched expression differences in source brain tissues. AD pathology had a more prominent association than biological sex with bdEV miRNA and tRNA components in late-stage AD brains. CONCLUSIONS: Our study provides further evidence that EV non-coding RNAs from human brain tissue, including but not limited to miRNAs, may be altered and contribute to AD pathogenesis.

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.

Transcriptional Signatures of Hippocampal Tau Pathology in Primary Age-Related Tauopathy and Alzheimer's Disease.

Background: Tau pathology is common in age-related neurodegenerative diseases. Tau pathology in primary age-related tauopathy (PART) and in Alzheimer's disease (AD) has a similar biochemical structure and anatomic distribution, which is distinct from tau pathology in other diseases. However, the molecular changes associated with intraneuronal tau pathology in PART and AD, and whether these changes are similar in the two diseases, is largely unexplored. Methods: Using GeoMx spatial transcriptomics, mRNA was quantified in CA1 pyramidal neurons with tau pathology and adjacent neurons without tau pathology in 6 cases of PART and 6 cases of AD, and compared to 4 control cases without pathology. Transcriptional changes were analyzed for differential gene expression and for coordinated patterns of gene expression associated with both disease state and intraneuronal tau pathology. Results: Synaptic gene changes and two novel gene expression signatures associated with intraneuronal tau were identified in PART and AD. Overall, gene expression changes associated with intraneuronal tau pathology were similar in PART and AD. Synaptic gene expression was decreased overall in neurons in AD and PART compared to control cases. However, this decrease was largely driven by neurons lacking tau pathology. Synaptic gene expression was increased in tau-positive neurons compared to tau-negative neurons in disease. Two novel gene expression signatures associated with intraneuronal tau were identified by examining coordinated patterns of gene expression. Genes in the up-regulated expression pattern were enriched in calcium regulation and synaptic function pathways, specifically in synaptic exocytosis. These synaptic gene changes and intraneuronal tau expression signatures were confirmed in a published transcriptional dataset of cortical neurons with tau pathology in AD. Conclusions: PART and AD show similar transcriptional changes associated with intraneuronal tau pathology in CA1 pyramidal neurons, raising the possibility of a mechanistic relationship between the tau pathology in the two diseases. Intraneuronal tau pathology was also associated with increased expression of genes associated with synaptic function and calcium regulation compared to tau-negative disease neurons. The findings highlight the power of molecular analysis stratified by pathology in neurodegenerative disease and provide novel insight into common molecular pathways associated with intraneuronal tau in PART and AD.