Pathophysiology characterization of Alzheimer's disease in South China's aging population: for the Greater-Bay-Area Healthy Aging Brain Study (GHABS).

INTRODUCTION: The Guangdong-Hong Kong-Macao Greater-Bay-Area of South China has an 86 million population and faces a significant challenge of Alzheimer's disease (AD). However, the characteristics and prevalence of AD in this area are still unclear due to the rarely available community-based neuroimaging AD cohort. METHODS: Following the standard protocols of the Alzheimer's Disease Neuroimaging Initiative, the Greater-Bay-Area Healthy Aging Brain Study (GHABS) was initiated in 2021. GHABS participants completed clinical assessments, plasma biomarkers, genotyping, magnetic resonance imaging (MRI), ß-amyloid (Aß) positron emission tomography (PET) imaging, and tau PET imaging. The GHABS cohort focuses on pathophysiology characterization and early AD detection in the Guangdong-Hong Kong-Macao Greater Bay Area. In this study, we analyzed plasma Aß42/Aß40 (A), p-Tau181 (T), neurofilament light, and GFAP by Simoa in 470 Chinese older adults, and 301, 195, and 70 had MRI, Aß PET, and tau PET, respectively. Plasma biomarkers, Aß PET, tau PET, hippocampal volume, and temporal-metaROI cortical thickness were compared between normal control (NC), subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia groups, controlling for age, sex, and APOE-ε4. The prevalence of plasma A/T profiles and Aß PET positivity were also determined in different diagnostic groups. RESULTS: The aims, study design, data collection, and potential applications of GHABS are summarized. SCD individuals had significantly higher plasma p-Tau181 and plasma GFAP than the NC individuals. MCI and dementia patients showed more abnormal changes in all the plasma and neuroimaging biomarkers than NC and SCD individuals. The frequencies of plasma A+/T+ (NC; 5.9%, SCD: 8.2%, MCI: 25.3%, dementia: 64.9%) and Aß PET positivity (NC: 25.6%, SCD: 22.5%, MCI: 47.7%, dementia: 89.3%) were reported. DISCUSSION: The GHABS cohort may provide helpful guidance toward designing standard AD community cohorts in South China. This study, for the first time, reported the pathophysiology characterization of plasma biomarkers, Aß PET, tau PET, hippocampal atrophy, and AD-signature cortical thinning, as well as the prevalence of Aß PET positivity in the Guangdong-Hong Kong-Macao Greater Bay Area of China. These findings provide novel insights into understanding the characteristics of abnormal AD pathological changes in South China's older population.

Association of ß-Amyloid, Microglial Activation, Cortical Thickness, and Metabolism in Older Adults Without Dementia.

BACKGROUND AND OBJECTIVES: Plasma ß-amyloid42 (Aß42)/Aß40 levels have shown promise in identifying Aß-PET positive individuals. This study explored the concordance and discordance of plasma Aß42/Aß40 positivity (Plasma±) with CSF Aß42/Aß40 positivity (CSF±) and Aß-PET positivity (PET±) in older adults without dementia. Associations of Aß deposition, cortical thickness, glucose metabolism, and microglial activation were also investigated. METHODS: We selected participants without dementia who had concurrent plasma Aß42/Aß40 and Aß-PET scans from the Alzheimer's Disease Neuroimaging Initiative cohort. Participants were categorized into Plasma±/PET± based on thresholds of composite 18F-florbetapir (FBP) standardized uptake value ratio (SUVR) ≥1.11 and plasma Aß42/Aß40 ≤0.1218. Aß-PET-negative individuals were further divided into Plasma±/CSF± (CSF Aß42/Aß40 ≤0.138), and the concordance and discordance of Aß42/Aß40 in the plasma and CSF were investigated. Baseline and slopes of regional FBP SUVR were compared among Plasma±/PET± groups, and associations of regional FBP SUVR, FDG SUVR, cortical thickness, and CSF soluble Triggering Receptor Expressed on Myeloid Cell 2 (sTREM2) levels were analyzed. RESULTS: One hundred eighty participants (mean age 72.7 years, 51.4% female, 96 cognitively unimpaired, and 84 with mild cognitive impairment) were included. We found that the proportion of Plasma+/PET- individuals was 6.14 times higher (odds ratio (OR) = 6.143, 95% confidence interval (CI) 2.740-16.185, p < 0.001) than that of Plasma-/PET+ individuals, and Plasma+/CSF- individuals showed 8.5 times larger percentage (OR = 8.5, 95% CI: 3.031-32.974, p < 0.001) than Plasma-/CSF+ individuals in Aß-PET-negative individuals. Besides, Plasma+/PET- individuals exhibited faster (p < 0.05) Aß accumulation predominantly in bilateral banks of superior temporal sulcus (BANKSSTS) and supramarginal, and superior parietal cortices compared with Plasma-/PET- individuals, despite no difference in baseline FBP SUVRs. In Plasma+/PET+ individuals, higher CSF sTREM2 levels correlated with slower BANKSSTS Aß accumulation (standardized ß (ßstd) = -0.418, 95% CI -0.681 to -0.154, p = 0.002). Conversely, thicker cortical thickness and higher glucose metabolism in supramarginal and superior parietal cortices were associated with faster (p < 0.05) CSF sTREM2 increase in Plasma+/PET- individuals rather than in Plasma+/PET+ individuals. DISCUSSION: These findings suggest that plasma Aß42/Aß40 abnormalities may predate CSF Aß42/Aß40 and Aß-PET abnormalities. Higher sTREM2-related microglial activation is linked to thicker cortical thickness and higher metabolism in early amyloidosis stages but tends to mitigate Aß accumulation primarily at relatively advanced stages.

Microglial Reactivity Correlates with Presynaptic Loss Independent of ß-Amyloid and Tau.

OBJECTIVE: Triggering receptor expressed on myeloid cells-2 (TREM2) and progranulin (PGRN) are critical regulators of microglia activation and can be detected in cerebrospinal fluid (CSF). However, whether microglial reactivity is detrimental or neuroprotective for Alzheimer disease (AD) is still debatable. METHODS: We identified 663 participants with baseline ß-amyloid (Aß) positron emission tomography (PET) and CSF biomarker data, including phosphorylated tau181 (p-Tau181), soluble TREM2 (sTREM2), PGRN, and growth-associated protein-43 (GAP-43). Among them, 254 participants had concurrent longitudinal CSF biomarkers. We used multivariate regression analysis to study the associations of CSF microglial biomarkers with Aß PET, CSF p-Tau181, and CSF GAP-43 cross-sectionally and longitudinally. A Chinese aging cohort's independent CSF samples (n = 65) were analyzed as a validation. RESULTS: Higher baseline levels of CSF microglial biomarkers were related to faster rates of CSF sTREM2 increase and CSF PGRN decrease. Elevated CSF p-Tau181 was associated with higher levels of CSF microglial biomarkers and faster rates of CSF sTREM2 increase and CSF PGRN decrease. In both cohorts, higher Aß burden was associated with attenuated CSF p-Tau181 effects on CSF microglial biomarker increases. Independent of Aß PET and CSF p-Tau181 pathologies, higher levels of CSF sTREM2 but not CSF PGRN were related to elevated CSF GAP-43 levels and faster rates of CSF GAP-43 increase. INTERPRETATION: These findings suggest that higher Aß burden may attenuate the p-Tau-associated microglial responses, and TREM2-related microglial reactivity may independently correlate with GAP-43-related presynaptic loss. This study highlights the two-edged role of microglial reactivity in AD and other neurodegenerative diseases. ANN NEUROL 2024;95:917-928.

GV-971 attenuates α-Synuclein aggregation and related pathology.

RATIONALE: Synucleinopathies, including Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), share a distinct pathological feature, that is, a widespread accumulation of α-synuclein (α-syn) in the brain. There is a significant clinical unmet need for disease-modifying treatments for synucleinopathies. Recently, a seaweed-derived mixture of oligosaccharides sodium oligomannate, GV-971, was approved for Phase 2 clinical trials for PD. This study aimed to further evaluate the therapeutic effects of GV-971 on synucleinopathies using cellular and animal models and explore its associated molecular mechanisms. METHODS: α-Syn aggregation was assessed, in vitro and ex vivo, by ThT assay. A dopaminergic neuron cell line, Prnp-SNCAA53T mice, and brain slices from PD and DLB patients were used to determine the efficacy of GV-971 in ameliorating α-syn pathology. Measurements of motor functions, including pole, cylinder, and rotarod tests, were conducted on Prnp-SNCAA53T mice 4 weeks after intragastric administration of GV-971 (200 mg day-1 kg-1 ). RESULTS: GV-971 effectively prevented α-syn aggregation and even disassembled pre-aggregated α-syn fibrils, in vitro and ex vivo. In addition, GV-971 was able to rescue α-syn-induced neuronal damage and reduced release of extracellular vesicles (EVs), likely via modulating Alix expression. In the Prnp-SNCAA53T mouse model, when treated at the age of 5 months, GV-971 significantly decreased α-syn deposition in the cortex, midbrain, and cerebellum regions, along with ameliorating the motor dysfunctions. CONCLUSIONS: Our results indicate that GV-971, when administered at a relatively early stage of the disease process, significantly reduced α-syn accumulation and aggregation in Prnp-SNCAA53T mice. Furthermore, GV-971 corrected α-syn-induced inhibition of EVs release in neurons, contributing to neuronal protection. Future studies are needed to further assess GV-971 as a promising disease-modifying therapy for PD and other synucleinopathies.

Erythrocytic α-Synuclein and the Gut Microbiome: Kindling of the Gut-Brain Axis in Parkinson's Disease.

BACKGROUND: Progressive spreading of α-synuclein via gut-brain axis has been hypothesized in the pathogenesis of Parkinson's disease (PD). However, the source of seeding-capable α-synuclein in the gastrointestinal tract (GIT) has not been fully investigated. Additionally, the mechanism by which the GIT microbiome contributes to PD pathogenesis remains to be characterized. OBJECTIVES: We aimed to investigate whether blood-derived α-synuclein might contribute to PD pathology via a gut-driven pathway and involve GIT microbiota. METHODS: The GIT expression of α-synuclein and the transmission of extracellular vesicles (EVs) derived from erythrocytes/red blood cells (RBCs), with their cargo α-synuclein, to the GIT were explored with various methods, including radioactive labeling of RBC-EVs and direct analysis of the transfer of α-synuclein protein. The potential role of microbiota on the EVs transmission was further investigated by administering butyrate, the short-chain fatty acids produced by gut microbiota and studying mice with different α-synuclein genotypes. RESULTS: This study demonstrated that RBC-EVs can effectively transport α-synuclein to the GIT in a region-dependent manner, along with variations closely associated with regional differences in the expression of gut-vascular barrier markers. The investigation further revealed that the infiltration of α-synuclein into the GIT was influenced significantly by butyrate and α-synuclein genotypes, which may also affect the GIT microbiome directly. CONCLUSION: By demonstrating the transportation of α-synuclein through RBC-EVs to the GIT, and its potential association with gut-vascular barrier markers and gut microbiome, this work highlights a potential mechanism by which RBC α-synuclein may impact PD initiation and/or progression. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Dry season temperature and rainy season precipitation significantly affect the spatio-temporal pattern of rubber plantation phenology in Yunnan province.

The ongoing global warming trajectory poses extensive challenges to plant ecosystems, with rubber plantations particularly vulnerable due to their influence on not only the longevity of the growth cycle and rubber yield, but also the complex interplay of carbon, water, and energy exchanges between the forest canopy and atmosphere. However, the response mechanism of phenology in rubber plantations to climate change remains unclear. This study concentrates on sub-optimal environment rubber plantations in Yunnan province, Southwest China. Utilizing the Google Earth Engine (GEE) cloud platform, multi-source remote sensing images were synthesized at 8-day intervals with a spatial resolution of 30-meters. The Normalized Difference Vegetation Index (NDVI) time series was reconstructed using the Savitzky-Golay (S-G) filter, coupled with the application of the seasonal amplitude method to extract three crucial phenological indicators, namely the start of the growing season (SOS), the end of the growing season (EOS), and the length of the growing season (LOS). Linear regression method, Pearson correlation coefficient, multiple stepwise regression analysis were used to extract of the phenology trend and find the relationship between SOS, EOS and climate factors. The findings demonstrated that 1) the phenology of rubber plantations has undergone dynamic changes over the past two decades. Specifically, the SOS advanced by 9.4 days per decade (R2 = 0.42, p< 0.01), whereas the EOS was delayed by 3.8 days per decade (R2 = 0.35, p< 0.01). Additionally, the LOS was extended by 13.2 days per decade (R2 = 0.55, p< 0.01); 2) rubber phenology demonstrated a notable sensitivity to temperature fluctuations during the dry season and precipitation patterns during the rainy season. The SOS advanced 2.0 days (r =-0.19, p< 0.01) and the EOS advanced 2.8 days (r =-0.35, p< 0.01) for every 1°C increase in the cool-dry season. Whereas a 100 mm increase in rainy season precipitation caused the SOS to be delayed by 2.0 days (r = 0.24, p< 0.01), a 100 mm increase in hot-dry season precipitation caused the EOS to be advanced by 7.0 days (r =-0.28, p< 0.01); 3) rubber phenology displayed a legacy effect of preseason climate variations. Changes in temperature during the fourth preseason month and precipitation during the fourth and eleventh preseason months are predominantly responsible for the variation in SOS. Meanwhile, temperature changes during the second, fourth, and ninth preseason months are primarily responsible for the variation in EOS. The study aims to enhance our understanding of how rubber plantations respond to climate change in sub-optimal environments and provide valuable insights for sustainable rubber production management in the face of changing environmental conditions.

Association of APOE-ε4 and GAP-43-related presynaptic loss with ß-amyloid, tau, neurodegeneration, and cognitive decline.

Apolipoprotein E-ε4 (APOE-ε4) carriers had elevated cerebrospinal fluid (CSF) presynaptic protein growth-associated protein-43 (GAP-43), but the underlying mechanism is not fully understood. We investigated how the APOE-ε4 genotype affects the baseline and longitudinal changes in CSF GAP-43 and their associations with ß-amyloid positron emission tomography (Aß PET), CSF phosphorylated tau 181 (p-Tau181), neurodegeneration, and cognitive decline. Compared to APOE-ε4 non-carriers, APOE-ε4 carriers had higher baseline levels and faster rates of increases in Aß PET, CSF p-Tau181, and CSF GAP-43. Both higher baseline levels and faster rates of increase in CSF GAP-43 were associated with greater baseline Aß PET and CSF p-Tau181, which fully mediated the APOE-ε4 effect on CSF GAP-43 elevations. Independent of Aß PET and CSF p-Tau181, APOE-ε4 carriage was associated with exacerbated GAP-43-related longitudinal hippocampal atrophy and cognitive decline, especially in Aß+ participants (GAP-43 × time × APOE-ε4). These findings suggest that the APOE-ε4 effect on GAP-43-related presynaptic dysfunction is mediated by primary Alzheimer's pathologies and independently correlates to hippocampal atrophy and cognitive decline in the future.

α-Synuclein-carrying astrocytic extracellular vesicles in Parkinson pathogenesis and diagnosis.

BACKGROUND: The accumulation of α-synuclein (α-syn), an essential step in PD development and progression, is observed not only in neurons but also in glia, including astrocytes. The mechanisms regulating astrocytic α-syn level and aggregation remain unclear. More recently, it has been demonstrated that a part of α-syn spreading occurs through extracellular vesicles (EVs), although it is unknown whether this process is involved in astrocytes of PD. It is known, however, that EVs derived from the central nervous system exist in the blood and are extensively explored as biomarkers for PD and other neurodegenerative disorders. METHODS: Primary astrocytes were transfected with A53T α-syn plasmid or exposed to α-syn aggregates. The level of astrocyte-derived EVs (AEVs) was assessed by nanoparticle tracking analysis and immunofluorescence. The lysosomal function was evaluated by Cathepsin assays, immunofluorescence for levels of Lamp1 and Lamp2, and LysoTracker Red staining. The Apogee assays were optimized to measure the GLT-1+ AEVs in clinical cohorts of 106 PD, 47 multiple system atrophy (MSA), and 103 healthy control (HC) to test the potential of plasma AEVs as a biomarker to differentiate PD from other forms of parkinsonism. RESULTS: The number of AEVs significantly increased in primary astrocytes with α-syn deposition. The mechanism of increased AEVs was partially attributed to lysosomal dysfunction. The number of α-syn-carrying AEVs was significantly higher in patients with PD than in HC and MSA. The integrative model combining AEVs with total and aggregated α-syn exhibited efficient diagnostic power in differentiating PD from HC with an AUC of 0.915, and from MSA with an AUC of 0.877. CONCLUSIONS: Pathological α-syn deposition could increase the astrocytic secretion of EVs, possibly through α-syn-induced lysosomal dysfunction. The α-syn-containing AEVs in the peripheral blood may be an effective biomarker for clinical diagnosis or differential diagnosis of PD.

Diversity and assembly of root-associated microbiomes of rubber trees.

Introduction: Understanding the diversity and assembly of the microbiomes of plant roots is crucial to manipulate them for sustainable ecosystem functioning. However, there are few reports about microbial communities at a continuous fine-scale of roots for rubber trees. Methods: We investigate the structure, diversity, and assembly of bacterial and fungal communities for the soil (non-rhizosphere), rhizosphere, and rhizoplane as well as root endosphere of rubber trees using the amplicon sequencing of 16S ribosomal ribonucleic acid (rRNA) and Internally Transcribed Spacer (ITS) genes. Results: We show that 18.69% of bacterial and 20.20% of fungal operational taxonomic units (OTUs) in the rhizoplane derived from the endosphere and 20.64% of bacterial and 20.60% of fungal OTUs from the soil. This suggests that the rhizoplane microbial community was a mixed community of soil and endosphere microbial communities and that microorganisms can disperse bidirectionally across different compartments of the plant root. On the other hand, in the absence of an enrichment or depletion of core bacterial and fungal OTUs in the rhizosphere, little differences in microbial composition as well as a more shared microbial network structure between the soil and the rhizosphere support the theory that the rhizosphere microbial community is a subset of the soil community. A large number of functional genes (such as nitrogen fixation and nitrite reduction) and more enriched core OTUs as well as a less stable but more complex network structure were observed in the rhizoplane of rubber tree roots. This demonstrated that the rhizoplane is the most active root compartment and a hotspot for plant-soil-environment interactions. In addition, bacterial and fungal communities in the rhizoplane were more stochastic compared to the rhizosphere and soil. Discussion: Our study expands our understanding of root-associated microbial community structure and function, which may provide the scientific basis for sustainable agriculture through biological process management.

Diversified land conversion deepens understanding of impacts of rapid rubber plantation expansion on plant diversity in the tropics.

Understanding the status and changes of plant diversity in rubber (Hevea brasiliensis) plantations is essential for sustainable plantation management in the context of rapid rubber expansion in the tropics, but remains very limited at the continental scale. In this study, we investigated plant diversity from 10-meter quadrats in 240 different rubber plantations in the six countries of the Great Mekong Subregion (GMS)-where nearly half of the world's rubber plantations are located-and analyzed the influence of original land cover types and stand age on plant diversity using Landsat and Sentinel-2 satellite imagery since the late 1980s. The results indicate that the average plant species richness of rubber plantations is 28.69 ± 7.35 (1061 species in total, of which 11.22 % are invasive), approximating half the species richness of tropical forests but roughly double that of the intensively managed croplands. Time-series satellite imagery analysis revealed that rubber plantations were primarily established in place of cropland (RPC, 37.72 %), old rubber plantations (RPORP, 27.63 %), and tropical forests (RPTF, 24.12 %). Plant species richness in RPTF (34.02 ± 7.62) was significantly (p < 0.001) higher than that in RPORP (26.41 ± 7.02) and RPC (26.34 ± 5.37). More importantly, species richness can be maintained for the duration of the 30-year economic cycle, and the number of invasive species decreases as the stand ages. Given diverse land conversions and changes in stand age, the total loss of species richness due to rapid rubber expansion in the GMS was 7.29 %, which is far below the traditional estimates that only consider tropical forest conversion. In general, maintaining higher species richness at the earliest stages of cultivation has significant implications for biodiversity conservation in rubber plantations.

Presynaptic membrane protein dysfunction occurs prior to neurodegeneration and predicts faster cognitive decline.

INTRODUCTION: Although presynaptic loss measured by cerebrospinal fluid (CSF) growth-associated protein-43 (GAP-43) is significantly involved in Alzheimer's disease (AD), the sequential association between CSF GAP-43 and AD-typical neurodegeneration is poorly understood. METHODS: We compared baseline CSF GAP-43 levels (n = 730) and longitudinal CSF GAP-43 changes (n = 327) in various biological stages of AD, and investigated their relationships with cross-sectional and longitudinal measures of residual hippocampal volume, 18 F-fluorodeoxyglucose PET, regional gray matter volume and cortical thickness, and cognition. RESULTS: Elevated CSF GAP43 levels were significantly associated with faster rates of hippocampal atrophy, AD-signature hypometabolism and cortical thinning, and middle temporal gray matter atrophy-related and AD-signature hypometabolism-related cognitive decline. In contrast, baseline levels of all these neurodegeneration biomarkers did not predict longitudinal CSF GAP-43 increases. DISCUSSION: These findings suggest that presynaptic loss may occur prior to neurodegeneration, highlighting the importance of lowing tau aggregation and tau-related synaptic dysfunction in elderly adults and AD patients.

Space Rather than Seasonal Changes Explained More of the Spatiotemporal Variation of Tropical Soil Microbial Communities.

Soil microbiomes play an essential role in maintaining soil geochemical cycle and function. Although there have been some reports on the diversity patterns and drivers of the tropical forest soil microbial community, how space and seasonal changes affect spatiotemporal distribution at the regional scales are poorly understood. Based on 260 soil samples, we investigated the spatiotemporal patterns of rubber plantations and rainforest soil microbial communities across the whole of Hainan Island, China during the dry and rainy seasons. We examined soil bacterial and fungal composition and diversity and the main drivers of these microbes using Illumina sequencing and assembly. Our results revealed that the diversity (both alpha and beta) spatiotemporal variation in microbial communities is highly dependent on regional location rather than seasonal changes. For example, the site explained 28.5% and 37.2% of the variation in alpha diversity for soil bacteria and fungi, respectively, and explained 34.6% of the bacterial variance and 14.3% of the fungal variance in beta diversity. Soil pH, mean annual temperature, and mean annual precipitation were the most important factors associated with the distribution of soil microbial communities. Furthermore, we identified that variations in edaphic (e.g., soil pH) and climatic factors (e.g., mean annual temperature [MAT] and mean annual precipitation [MAP]) were mainly caused by regional sites (P < 0.001). Collectively, our work provides empirical evidence that space, rather than seasonal changes, explained more of the spatiotemporal variation of soil microbial communities in tropical forests, mediated by regional location-induced changes in climatic factors and edaphic properties. IMPORTANCE The soil microbiomes communities of the two forests were not only affected by environmental factors (e.g., edaphic and climatic factors), but also by different dominant geographic factors. In particular, our work showed that spatial variation in bacterial and fungal community composition was mainly dominated by edaphic properties (e.g., pH) and climatic factors (e.g., MAT and MAP). Moreover, the environmental factors were mainly explained by geographic location effect rather than by seasonal effect, and environmental dissimilarity significantly increased with geographic distance. In conclusion, our study provides solid empirical evidence that space rather than season explained more of the spatiotemporal variation of soil microbial communities in the tropical forest.

Association of Presynaptic Loss with Alzheimer's Disease and Cognitive Decline.

OBJECTIVE: Increased presynaptic dysfunction measured by cerebrospinal fluid (CSF) growth-associated protein-43 (GAP43) may be observed in Alzheimer's disease (AD), but how CSF GAP43 increases relate to AD-core pathologies, neurodegeneration, and cognitive decline in AD requires further investigation. METHODS: We analyzed 731 older adults with baseline ß-amyloid (Aß) positron emission tomography (PET), CSF GAP43, CSF phosphorylated tau181 (p-Tau181 ), and 18 F-fluorodeoxyglucose PET, and longitudinal residual hippocampal volume and cognitive assessments. Among them, 377 individuals had longitudinal 18 F-fluorodeoxyglucose PET, and 326 individuals had simultaneous longitudinal CSF GAP43, Aß PET, and CSF p-Tau181 data. We compared baseline and slopes of CSF GAP43 among different stages of AD, as well as their associations with Aß PET, CSF p-Tau181 , residual hippocampal volume, 18 F-fluorodeoxyglucose PET, and cognition cross-sectionally and longitudinally. RESULTS: Regardless of Aß positivity and clinical diagnosis, CSF p-Tau181 -positive individuals showed higher CSF GAP43 concentrations (p < 0.001) and faster rates of CSF GAP43 increases (p < 0.001) compared with the CSF p-Tau181 -negative individuals. Moreover, higher CSF GAP43 concentrations and faster rates of CSF GAP43 increases were strongly related to CSF p-Tau181 independent of Aß PET. They were related to more rapid hippocampal atrophy, hypometabolism, and cognitive decline (p < 0.001), and predicted the progression from MCI to dementia (area under the curve for baseline 0.704; area under the curve for slope 0.717) over a median 4 years of follow up. INTERPRETATION: Tau aggregations rather than Aß plaques primarily drive presynaptic dysfunction measured by CSF GAP43, which may lead to sequential neurodegeneration and cognitive impairment in AD or neurodegenerative diseases. ANN NEUROL 2022;92:1001-1015.

Phyllosphere fungal communities of rubber trees exhibited biogeographical patterns, but not bacteria.

Phyllosphere microbiomes play an essential role in maintaining host health and productivity. Still, the diversity patterns and the drivers for the phyllosphere microbial community of the tropical cash crop Rubber tree (Hevea brasiliensis) - are poorly understood. We sampled the phyllosphere of field-grown rubber trees in South China. We examined the phyllosphere bacterial and fungal composition, diversity and main drivers of these microbes using the Illumina® sequencing and assembly. Fungal communities were distinctly different in different climatic regions (i.e. Xishuangbanna and Hainan Island) and climatic factors, especially mean annual temperature, and they were the main driving factors of foliar fungal communities, indicating fungal communities showed a geographical pattern. Significant differences of phyllosphere bacterial communities were detected in different habitats (i.e. endophytic and epiphytic). Most of the differences in taxa composition came from Firmicutes spp., which have been assigned as nitrogen-fixing bacteria. Since these bacteria cannot penetrate the cuticle like fungi, the abundant epiphytic Firmicutes spp. may supplement the deficiency of nitrogen acquisition. And the main factor influencing endophytic bacteria were internal factors, such as total nitrogen, total phosphorus and water content of leaves. External factors (i.e. climate) were the main driving force for epiphytic bacteria community assembly. Our work provides empirical evidence that the assembly of phyllosphere bacterial and fungal differed, which creates a precedent for preventing and controlling rubber tree diseases and pests and rubber tree yield improvement.

Astrocytic VEGFA: An essential mediator in blood-brain-barrier disruption in Parkinson's disease.

The integrity of blood-brain-barrier (BBB) is essential for normal brain functions, synaptic remodeling, and angiogenesis. BBB disruption is a common pathology during Parkinson's disease (PD), and has been hypothesized to contribute to the progression of PD. However, the molecular mechanism of BBB disruption in PD needs further investigation. Here, A53T PD mouse and a 3-cell type in vitro BBB model were used to study the roles of α-synuclein (α-syn) in BBB disruption with the key results confirmed in the brains of PD patients obtained at autopsy. The A53T PD mouse studies showed that the expression of tight junction-related proteins decreased, along with increased vascular permeability and accumulation of oligomeric α-syn in activated astrocytes in the brain. The in vitro BBB model studies demonstrated that treatment with oligomeric α-syn, but not monomeric or fibrillar α-syn, resulted in significant disruption of BBB integrity. This process involved the expression and release of vascular endothelial growth factor A (VEGFA) and nitric oxide (NO) from oligomeric α-syn treated astrocytes. Increased levels of VEGFA and iNOS were also observed in the brain of PD patients. Blocking the VEGFA signaling pathway in the in vitro BBB model effectively protected the barrier against the harmful effects of oligomeric α-syn. Finally, the protective effects on BBB integrity associated with inhibition of VEGFA signaling pathway was also confirmed in PD mice. Taken together, our study concluded that oligomeric α-syn is critically involved in PD-associated BBB disruption, in a process that is mediated by astrocyte-derived VEGFA.

Effects of rubber plantations on soil physicochemical properties on Hainan Island, China.

Recent and rapid expansion of rubber [Hevea brasiliensis (Willd. ex A. Juss.) Müll. Arg.] plantations requires understanding their effects on soil physicochemical properties and soil quality. An ideal testbed for analyzing such land-use change and its impacts is Hainan Island, the largest tropical island in China, which in recent decades has seen a dramatic expansion in the rubber industry. Based on 14 soil physicochemical properties at two soil depths (0-20 and 20-40 cm), a comprehensive assessment index was established using principal component analysis to assess soil qualities under rubber plantations (RPs; monoculture and intercropping) and five additional land-use types (areca palm [Areca L.], eucalyptus [Eucalyptus loxophleba Benth.] and banana [Musa L.] plantations, secondary forest, and tropical rainforest [TR]). The following results were obtained: (a) total porosity, ammoniacal N, total P, available P, and soil organic matter were vital soil physicochemical properties contributing to the comprehensive assessment index; (b) the comprehensive assessment indices of RPs were significantly lower than those of TR and areca palm plantation; (c) intercropping improves most soil physicochemical properties in RPs comparing monoculture and intercropped RPs; and (d) redundancy analysis demonstrated that land-use type interacted with climatic, geographical, and edaphic factors and collectively explained about half of the variation in the soil physicochemical properties across the study area. Deteriorating soil quality by converting TR to RPs and other land-use types provides another reason to protect TRs, especially on area-limited islands like Hainan.

Seasonal changes impact soil bacterial communities in a rubber plantation on Hainan Island, China.

Rubber plantations have expanded rapidly over the past 20 years in tropical Asia and their impacts on regional ecosystems have garnered much concern. While much attention has been given to the negative impacts on aboveground diversity and function, the belowground bacterial soil community has received much less attention. Here, we investigated the community composition and diversity of soil bacteria of rubber plantations on Hainan Island in south China. The goals of the study were to describe changes in bacterial compositions and diversity across seasons. We found that seasonality defined by differences in rainfall amount strongly influenced bacterial communities. At both the Phylum and Family levels, we found significant differences in the total number of taxa, as well as the composition of the community as a function of season. Diversity of soil samples in the dry-rainy season was highest of three seasons, suggesting that bacterial structure was more sensitive in alternate periods of season. Diversity in the rainy season was substantial lower than in dry season. Results from a redundancy analysis showed that seasonal changes explained the largest part (31.9%) of the total variance of bacterial community composition. In conclusion, seasonal change had the greatest influence on bacterial communities, which overshadowed the effects of soil nutrient as well as other factors, and controls the bacterial communities in soils of RP in tropical region of Hainan.

On the ratio of intercellular to ambient CO2 (c i/c a) derived from ecosystem flux.

The ratio of intercellular to ambient CO2 concentrations (c i/c a) plays a key role in ecophysiology, micrometeorology, and global climatic change. However, systematic investigation on c i/c a variation and its determinants are rare. Here, the c i/c a was derived from measuring ecosystem fluxes in an even-aged monoculture of rubber trees (Hevea brasiliensis). We tested whether c i/c a is constant across environmental gradients and if not, which dominant factors control c i/c a variations. Evidence indicates that c i/c a is not a constant. The c i/c a exhibits a clear "V"-shaped diurnal pattern and varies across the environmental gradient. Water vapor pressure deficit (D) is the dominant factor controls over the c i/c a variations. c i/c a consistently decreases with increasing D. c i/c a decreases with square root of D as predicted by the optimal stomatal model. The D-driving single-variable model could simulate c i/c a as well as that of sophisticated model. Many variables function on longer timescales than a daily cycle, such as soil water content, could improve c i/c a model prediction ability. Ecosystem flux can be effectively used to calculate c i/c a and use it to better understand various natural cycles.

Rubber Trees Demonstrate a Clear Retranslocation Under Seasonal Drought and Cold Stresses.

Having been introduced to the northern edge of Asian tropics, the rubber tree (Hevea brasiliensis) has become deciduous in this climate with seasonal drought and cold stresses. To determine its internal nutrient strategy during leaf senescence and deciduous periods, we investigated mature leaf and senescent leaf nutrients, water-soluble soil nutrients and characteristics of soil microbiota in nine different ages of monoculture rubber plantations. Rubber trees demonstrate complicated retranslocation of N, P, and K during foliar turnover. Approximately 50.26% of leaf nutrients and 21.47% of soil nutrients were redistributed to the rubber tree body during the leaf senescence and withering stages. However, no significant changes in the structure- or function-related properties of soil microbes were detected. These nutrient retranslocation strategy may be important stress responses. In the nutrient retranslocation process, soil plays a dual role as nutrient supplier and nutrient "bank." Soil received the nutrients from abscised leaves, and also supplied nutrients to trees in the non-growth stage. Nutrient absorption and accumulation began before the leaves started to wither and fall.