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Background Meta‐analysis studies provided strong correlations between individuals’ histories of early‐life depression induced by stress and their risk of developing Alzheimer’s disease (AD) [Ownby RL et al., 2006]. While psychological stress is crucial for survival, it is unknown if maladaptive stress response may function as a risk factor in the onset and progression of AD. In this study using a murine model of AD, we tested the hypothesis that susceptibility to stress may promote cognitive deterioration and AD neuropathology. Method In this study 8‐week‐old WT and 5xFAD mice underwent a social defeat stress (RSDS) paradigm to identify differential susceptibility to stress as assessed anxiety or depression like behaviors for 2 weeks [Wang J et al., 2018], followed by novel object recognition test assessed by cognitive functions. CyTOF was used to profile peripheral immune homeostasis and unbiased RNA sequencing of hippocampal formation to assess association with changes in gene expression analyzed by CIBERSORTx deconvolution and IPA‐analysis. Result Following RSDS exposure, we found that 61.2% of 5xFAD mice showed susceptibility and only 38.8% of total 5xFAD mice revealed resilience to psychological stress. Interestingly the ratio of susceptibility was almost opposite in WT control littermates, as reflected by only 39.4% of susceptible mice. This suggests 5xFAD mice are more susceptible to psychological stress relative to WT control littermates at 11‐weeksage. Most importantly, within 5xFAD‐stressed mouse group, we found that only the susceptible‐5xFAD mice, but not the resilient‐5XFAD mice, exhibited acceleration of cognitive impairments relative to unstressed‐5xFAD at this pre‐pathological stage of AD. There was no statistically significant difference in cognitive impairment among susceptible, resilient or non‐stressed WT control littermates. To understand potential underlying mechanisms, we performed CyTOF to identify alteration of certain blood immune cell subtypes of susceptible‐5xFAD mice compared to resilient‐5xFAD mice. Interestingly, using CIBERSORTx deconvolution and IPA‐analysis of hippocampal formation RNA seq from susceptible‐5xFAD mice which are cognitive impaired revealed significant altered expression of genes associated of synaptic plasticity relative to resilient‐5xFAD mice. Conclusion Our study raises warnings for more investigation directed toward understanding of heterogeneity of responses when AD phenotype mice are assessed for behavior and molecular studies.

Background There is growing evidence that in many neurodegenerative disorders, cell‐to‐cell transmission of a pathological, misfolded protein, such as misfolding of α‐synuclein (α‐syn) in Parkinson’s disease (PD), may be a vehicle for the spreading of pathology throughout the brain. This misfolded protein, or seed, further induces misfolding of native proteins within the cell. Pathological misfolded proteins may exist in diverse conformations with distinct cellular and biochemical properties. We investigate whether microbiota‐derived metabolites may help attenuate the misfolding of α‐syn and thereby promote resilience against PD phenotypes. We identified six biologically available gut microbiota‐derived compounds (GMP10, GMP11, GMP26, GMP28, GMP39, and GMP44) for investigation. Method Using independent in vitro protein aggregation assays (e.g., photo‐induced cross‐linking of unmodified proteins assay, thioflavin‐T, fluorescence assay, and electron microscopy), we demonstrated that three of the compounds (GMP26, GMP44, GMP28), potently inhibit aggregations of monomeric α‐syn (or monomeric β‐amyloid peptides) into neurotoxic protein aggregates, in vitro. Result Based on evidence linking the c9orf72 gene with expansions of GGGGCC hexanucleotide repeats and PD, as well as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), we continue to test the neuroprotective ability of our compounds in vivo using a Drosophila model with overexpression of GGGGCC hexanucleotide repeats. Overexpression of 30 GGGGCC repeats in the Drosophila eye causes age‐dependent photoreceptor neurodegeneration. We treated Drosophila by mixing individual test compounds into the food. We found all six compounds significantly suppressed eye degeneration at 10 µM, with compounds GMP26 and GMP11 almost completely suppressing the eye phenotype. The comparative efficacy of the six compounds are GMP26 = GMP11 > GMP39 > GMP10 > GMP44 > GMP28. Conclusion Outcomes from our studies link gut microbiota with mechanisms underlying PD and suggest the feasibility of developing GMP26 as a means to simultaneously target both α‐syn misfolding and C9orf72 expansion to increase the likelihood of therapeutic efficacy in PD, ALS, FTD patients with C9orf72 expansion.

Background Climate change presents an escalating threat to life and health, particularly impacting vulnerable populations. Ambient particulate matter (PM) and extreme heat stress (HS) contribute independently and synergistically to severe health problems, including respiratory and cardiovascular diseases, neurodegenerative disorders, and increased mortality rates. Particulate matter with an aerodynamic diameter of 2.5 µm or smaller (PM2.5) exacerbates conditions such as asthma, heart disease, and neurodegenerative illnesses. Meanwhile, extreme heat can lead to heat‐related illnesses, aggravate existing chronic conditions, and heighten pollution levels. The combined exposure to PM and HS intensifies these negative health effects, underscoring the urgent need for effective public health interventions and policies, particularly for the elderly population, who are at a higher risk for Alzheimer's disease. Method In an experimental mouse model of early‐onset Alzheimer's disease (EOAD), we investigated the combined effects of exposure to extreme weather conditions, specifically ambient PM2.5 and heat stress. Result Our findings revealed that even short‐term exposure to these environmental factors disrupts energy metabolism and mitochondrial respiratory functions, which is linked to synaptic dysfunction in the hippocampus. Notably, we identified central mechanisms associated with impaired intestinal permeability and gut dysbiosis, affecting communication along the gut‐brain axis, examined through immune and inflammatory signaling alterations. Surprisingly, despite the significant disruption of metabolic and immune‐inflammatory pathways both centrally and peripherally, we found no cognitive decline at this early stage of exposure to environmental pollutants. Conclusion These results emphasize the urgent need to consider environmental factors in preventive public health strategies, even for individuals at risk of Alzheimer's disease who may not yet exhibit symptoms.

There is growing evidence that in many neurodegenerative disorders, cell-to-cell transmission of a pathological, misfolded protein, such as misfolding of α-synuclein (α-syn) in Parkinson's disease (PD), may be a vehicle for the spreading of pathology throughout the brain. This misfolded protein, or seed, further induces misfolding of native proteins within the cell. Pathological misfolded proteins may exist in diverse conformations with distinct cellular and biochemical properties. We investigate whether microbiota-derived metabolites may help attenuate the misfolding of α-syn and thereby promote resilience against PD phenotypes. We identified six biologically available gut microbiota-derived compounds (GMP10, GMP11, GMP26, GMP28, GMP39, and GMP44) for investigation. Using independent in vitro protein aggregation assays (e.g., photo-induced cross-linking of unmodified proteins assay, thioflavin-T, fluorescence assay, and electron microscopy), we demonstrated that three of the compounds (GMP26, GMP44, GMP28), potently inhibit aggregations of monomeric α-syn (or monomeric β-amyloid peptides) into neurotoxic protein aggregates, in vitro. Based on evidence linking the c9orf72 gene with expansions of GGGGCC hexanucleotide repeats and PD, as well as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), we continue to test the neuroprotective ability of our compounds in vivo using a Drosophila model with overexpression of GGGGCC hexanucleotide repeats. Overexpression of 30 GGGGCC repeats in the Drosophila eye causes age-dependent photoreceptor neurodegeneration. We treated Drosophila by mixing individual test compounds into the food. We found all six compounds significantly suppressed eye degeneration at 10 µM, with compounds GMP26 and GMP11 almost completely suppressing the eye phenotype. The comparative efficacy of the six compounds are GMP26 = GMP11 > GMP39 > GMP10 > GMP44 > GMP28. Outcomes from our studies link gut microbiota with mechanisms underlying PD and suggest the feasibility of developing GMP26 as a means to simultaneously target both α-syn misfolding and C9orf72 expansion to increase the likelihood of therapeutic efficacy in PD, ALS, FTD patients with C9orf72 expansion.

Background Lecanemab, a human IgG1 monoclonal antibody targeting oligomer, protofibrils and fibril forms of beta‐amyloid, has been reported to reduce amyloid pathology and improve impaired cognition after administration of a high dose (10 mg/kg) of the drug in Alzheimerʼs disease (AD) clinical trials. The purpose of this study was to investigate the therapeutic efficacy and the associated molecular mechanisms of a lower dose of lecanemab (1 mg/kg) with enhanced delivery via focused ultrasound (FUS) in a mouse model of AD. Method We used 6‐month‐old WT and 5xFAD mouse model. The FUS with microbubbles opened the blood– brain barrier (BBB) of the hippocampus for the delivery of lecanemab. The combined therapy of FUS and 1mg/kg of lecanemab was performed three times in total and each treatment was performed biweekly. Y‐maze test and immunohistochemical experimental methods were employed in this study. Result The FUS‐mediated BBB opening markedly increased the delivery of lecanemab into the brain by approximately 10 times in the brains. The combined treatment induced significantly less cognitive decline and decreased the level of amyloid plaques in the hippocampi of the 5×FAD mice compared with lecanemab alone. Combined treatment with FUS and lecanemab activated phagocytic microglia without hemorrhage in the hippocampi of 5×FAD mice. To understand potential underlying mechanisms, we performed RNA sequencing and identified that enriched canonical pathways including phagosome formation, neuroinflammation signaling and synaptic plasticity were altered in 5xFAD mice. Conclusion Our study elucidated that FUS‐mediated delivery of a low dose of lecanemab (1 mg/kg) decreases amyloid deposits and attenuates cognitive function deficits. We present an AD treatment strategy through the synergistic effect of the combined therapy of FUS and lecanemab.

Lecanemab, a human IgG1 monoclonal antibody targeting oligomer, protofibrils and fibril forms of beta-amyloid, has been reported to reduce amyloid pathology and improve impaired cognition after administration of a high dose (10 mg/kg) of the drug in Alzheimer's disease (AD) clinical trials. The purpose of this study was to investigate the therapeutic efficacy and the associated molecular mechanisms of a lower dose of lecanemab (1 mg/kg) with enhanced delivery via focused ultrasound (FUS) in a mouse model of AD. We used 6-month-old WT and 5xFAD mouse model. The FUS with microbubbles opened the blood- brain barrier (BBB) of the hippocampus for the delivery of lecanemab. The combined therapy of FUS and 1mg/kg of lecanemab was performed three times in total and each treatment was performed biweekly. Y-maze test and immunohistochemical experimental methods were employed in this study. The FUS-mediated BBB opening markedly increased the delivery of lecanemab into the brain by approximately 10 times in the brains. The combined treatment induced significantly less cognitive decline and decreased the level of amyloid plaques in the hippocampi of the 5×FAD mice compared with lecanemab alone. Combined treatment with FUS and lecanemab activated phagocytic microglia without hemorrhage in the hippocampi of 5×FAD mice. To understand potential underlying mechanisms, we performed RNA sequencing and identified that enriched canonical pathways including phagosome formation, neuroinflammation signaling and synaptic plasticity were altered in 5xFAD mice. Our study elucidated that FUS-mediated delivery of a low dose of lecanemab (1 mg/kg) decreases amyloid deposits and attenuates cognitive function deficits. We present an AD treatment strategy through the synergistic effect of the combined therapy of FUS and lecanemab.

Meta-analysis studies provided strong correlations between individuals' histories of early-life depression induced by stress and their risk of developing Alzheimer's disease (AD) [Ownby RL et al., 2006]. While psychological stress is crucial for survival, it is unknown if maladaptive stress response may function as a risk factor in the onset and progression of AD. In this study using a murine model of AD, we tested the hypothesis that susceptibility to stress may promote cognitive deterioration and AD neuropathology. In this study 8-week-old WT and 5xFAD mice underwent a social defeat stress (RSDS) paradigm to identify differential susceptibility to stress as assessed anxiety or depression like behaviors for 2 weeks [Wang J et al., 2018], followed by novel object recognition test assessed by cognitive functions. CyTOF was used to profile peripheral immune homeostasis and unbiased RNA sequencing of hippocampal formation to assess association with changes in gene expression analyzed by CIBERSORTx deconvolution and IPA-analysis. Following RSDS exposure, we found that 61.2% of 5xFAD mice showed susceptibility and only 38.8% of total 5xFAD mice revealed resilience to psychological stress. Interestingly the ratio of susceptibility was almost opposite in WT control littermates, as reflected by only 39.4% of susceptible mice. This suggests 5xFAD mice are more susceptible to psychological stress relative to WT control littermates at 11-weeksage. Most importantly, within 5xFAD-stressed mouse group, we found that only the susceptible-5xFAD mice, but not the resilient-5XFAD mice, exhibited acceleration of cognitive impairments relative to unstressed-5xFAD at this pre-pathological stage of AD. There was no statistically significant difference in cognitive impairment among susceptible, resilient or non-stressed WT control littermates. To understand potential underlying mechanisms, we performed CyTOF to identify alteration of certain blood immune cell subtypes of susceptible-5xFAD mice compared to resilient-5xFAD mice. Interestingly, using CIBERSORTx deconvolution and IPA-analysis of hippocampal formation RNA seq from susceptible-5xFAD mice which are cognitive impaired revealed significant altered expression of genes associated of synaptic plasticity relative to resilient-5xFAD mice. Our study raises warnings for more investigation directed toward understanding of heterogeneity of responses when AD phenotype mice are assessed for behavior and molecular studies.

Climate change presents an escalating threat to life and health, particularly impacting vulnerable populations. Ambient particulate matter (PM) and extreme heat stress (HS) contribute independently and synergistically to severe health problems, including respiratory and cardiovascular diseases, neurodegenerative disorders, and increased mortality rates. Particulate matter with an aerodynamic diameter of 2.5 µm or smaller (PM2.5) exacerbates conditions such as asthma, heart disease, and neurodegenerative illnesses. Meanwhile, extreme heat can lead to heat-related illnesses, aggravate existing chronic conditions, and heighten pollution levels. The combined exposure to PM and HS intensifies these negative health effects, underscoring the urgent need for effective public health interventions and policies, particularly for the elderly population, who are at a higher risk for Alzheimer's disease. In an experimental mouse model of early-onset Alzheimer's disease (EOAD), we investigated the combined effects of exposure to extreme weather conditions, specifically ambient PM2.5 and heat stress. Our findings revealed that even short-term exposure to these environmental factors disrupts energy metabolism and mitochondrial respiratory functions, which is linked to synaptic dysfunction in the hippocampus. Notably, we identified central mechanisms associated with impaired intestinal permeability and gut dysbiosis, affecting communication along the gut-brain axis, examined through immune and inflammatory signaling alterations. Surprisingly, despite the significant disruption of metabolic and immune-inflammatory pathways both centrally and peripherally, we found no cognitive decline at this early stage of exposure to environmental pollutants. These results emphasize the urgent need to consider environmental factors in preventive public health strategies, even for individuals at risk of Alzheimer's disease who may not yet exhibit symptoms.

We have detected in Cassini spacecraft data the signature of the periodic tidal stresses within Titan, driven by the eccentricity (e = 0.028) of its 16-day orbit around Saturn. Precise measurements of the acceleration of Cassini during six close flybys between 2006 and 2011 have revealed that Titan responds to the variable tidal field exerted by Saturn with periodic changes of its quadrupole gravity, at about 4% of the static value. Two independent determinations of the corresponding degree-2 Love number yield k 2 = 0.589 ± 0.150 and k 2 = 0.637 ± 0.224 (2σ). Such a large response to the tidal field requires that Titan's interior be deformable over time scales of the orbital period, in a way that is consistent with a global ocean at depth.