Nitrated α–Synuclein Immunity Accelerates Degeneration of Nigral Dopaminergic Neurons

The neuropathology of Parkinson's disease (PD) includes loss of dopaminergic neurons in the substantia nigra, nitrated alpha-synuclein (N-alpha-Syn) enriched intraneuronal inclusions or Lewy bodies and neuroinflammation. While the contribution of innate microglial inflammatory activities to disease are known, evidence for how adaptive immune mechanisms may affect the course of PD remains obscure. We reasoned that PD-associated oxidative protein modifications create novel antigenic epitopes capable of peripheral adaptive T cell responses that could affect nigrostriatal degeneration.Nitrotyrosine (NT)-modified alpha-Syn was detected readily in cervical lymph nodes (CLN) from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxicated mice. Antigen-presenting cells within the CLN showed increased surface expression of major histocompatibility complex class II, initiating the molecular machinery necessary for efficient antigen presentation. MPTP-treated mice produced antibodies to native and nitrated alpha-Syn. Mice immunized with the NT-modified C-terminal tail fragment of alpha-Syn, but not native protein, generated robust T cell proliferative and pro-inflammatory secretory responses specific only for the modified antigen. T cells generated against the nitrated epitope do not respond to the unmodified protein. Mice deficient in T and B lymphocytes were resistant to MPTP-induced neurodegeneration. Transfer of T cells from mice immunized with N-alpha-Syn led to a robust neuroinflammatory response with accelerated dopaminergic cell loss.These data show that NT modifications within alpha-Syn, can bypass or break immunological tolerance and activate peripheral leukocytes in draining lymphoid tissue. A novel mechanism for disease is made in that NT modifications in alpha-Syn induce adaptive immune responses that exacerbate PD pathobiology. These results have implications for both the pathogenesis and treatment of this disabling neurodegenerative disease

Small autonomous landers for studying the community ecology of nearshore submarine canyons

Nearshore submarine canyons are unique features that bring the deep sea close to shore, potentially functioning as highways connecting shallow and deep-sea ecosystems. To study their ecology, we developed two autonomous lander systems: a 2-sphere Picolander for exploratory deployments (< 3 days) and a 3-sphere Nanolander for longer deployments (> 1 week). Both landers were outfitted with a camera and lights system and a ZebraTech environmental sensor and collected paired physical and biological time series. Eleven lander deployments were completed ranging in length from 1-13 days at depths of 90-500 m, allowing assessment of how seafloor community diversity and composition changed with depth and time of day. We found that communities at 100 and 500 m were distinct from all other depths while the 300 m community was transitional between these depths and had the highest diversity, despite unexpectedly high turbidity. Additionally, we recorded clear diurnal patterns in fishes deeper than 300 m, as well as vertical migration of larval flatfish. This study also aimed to document the number and area of small submarine canyons off the coast of California and determine the extent of government protection of both large and small canyons. Small canyons were defined as features with a minimum depth of 200 m and incised 100 m into the slope. Applying this, 23 small canyons were identified, with features concentrated on the Central and Southern coast. By area, 27% of large canyons and 23% of small canyons were protected, with the inshore reaches of canyons receiving more protection than offshore. Because landers collect paired biological and physical data in hard to access areas, they may serve as powerful tools to inform management of these poorly studied deep-water habitats

Characterizing deepwater oxygen variability and seafloor community responses using a novel autonomous lander

Abstract. Studies on the impacts of climate change typically focus on changes to mean conditions. However, animals live in temporally variable environments that give rise to different exposure histories that can potentially affect their sensitivities to climate change. Ocean deoxygenation has been observed in nearshore, upper-slope depths in the Southern California Bight, but how these changes compare to the magnitude of natural O2 variability experienced by seafloor communities at short timescales is largely unknown. We developed a low-cost and spatially flexible approach for studying nearshore, deep-sea ecosystems and monitoring deepwater oxygen variability and benthic community responses. Using a novel, autonomous, hand-deployable Nanolander® with an SBE MicroCAT and camera system, high-frequency environmental (O2, T, estimated pH) and seafloor community data were collected at depths between 100 and 400 m off San Diego, CA, to characterize timescales of natural environmental variability, changes in O2 variability with depth, and community responses to O2 variability. Oxygen variability was strongly linked to tidal processes, and contrary to expectation, oxygen variability did not decline linearly with depth. Depths of 200 and 400 m showed especially high O2 variability; these conditions may give rise to greater community resilience to deoxygenation stress by exposing animals to periods of reprieve during higher O2 conditions and invoking physiological acclimation during low O2 conditions at daily and weekly timescales. Despite experiencing high O2 variability, seafloor communities showed limited responses to changing conditions at these shorter timescales. Over 5-month timescales, some differences in seafloor communities may have been related to seasonal changes in the O2 regime. Overall, we found lower-oxygen conditions to be associated with a transition from fish-dominated to invertebrate-dominated communities, suggesting this taxonomic shift may be a useful ecological indicator of hypoxia. Due to their small size and ease of use with small boats, hand-deployable Nanolanders can serve as a powerful capacity-building tool in data-poor regions for characterizing environmental variability and examining seafloor community sensitivity to climate-driven changes

Characterizing deepwater oxygen variability and seafloor community responses using a novel autonomous lander

Abstract. Studies on the impacts of climate change typically focus on changes to mean conditions. However, animals live in temporally variable environments that give rise to different exposure histories that can potentially affect their sensitivities to climate change. Ocean deoxygenation has been observed in nearshore, upper-slope depths in the Southern California Bight, but how these changes compare to the magnitude of natural O2 variability experienced by seafloor communities at short timescales is largely unknown. We developed a low-cost and spatially flexible approach for studying nearshore, deep-sea ecosystems and monitoring deepwater oxygen variability and benthic community responses. Using a novel, autonomous, hand-deployable Nanolander® with an SBE MicroCAT and camera system, high-frequency environmental (O2, T, estimated pH) and seafloor community data were collected at depths between 100 and 400 m off San Diego, CA, to characterize timescales of natural environmental variability, changes in O2 variability with depth, and community responses to O2 variability. Oxygen variability was strongly linked to tidal processes, and contrary to expectation, oxygen variability did not decline linearly with depth. Depths of 200 and 400 m showed especially high O2 variability; these conditions may give rise to greater community resilience to deoxygenation stress by exposing animals to periods of reprieve during higher O2 conditions and invoking physiological acclimation during low O2 conditions at daily and weekly timescales. Despite experiencing high O2 variability, seafloor communities showed limited responses to changing conditions at these shorter timescales. Over 5-month timescales, some differences in seafloor communities may have been related to seasonal changes in the O2 regime. Overall, we found lower-oxygen conditions to be associated with a transition from fish-dominated to invertebrate-dominated communities, suggesting this taxonomic shift may be a useful ecological indicator of hypoxia. Due to their small size and ease of use with small boats, hand-deployable Nanolanders can serve as a powerful capacity-building tool in data-poor regions for characterizing environmental variability and examining seafloor community sensitivity to climate-driven changes

Spies in the Deep: Ocean Landers Explore the Deep Sea

Below the surface layers of the ocean, there are ecosystems full of undiscovered life. Scientists love to ask questions like, “Who is there?” and “What are they doing?” An important question scientists are beginning to ask is, “How will these living things react to warmer waters, loss of oxygen, or pollution?” To answer these questions, scientists build equipment to observe life in the deep sea. We built an ocean lander named BEEBE, with a camera, sensors, and waterproof casing. BEEBE helped us study deep-sea ecosystems near the coast of California and learn about the animals that live there. We can use what we learned to recognize vulnerable communities and the threats some ocean animals face. An ocean lander like BEEBE can be a great tool to learn more about coastal, deep-sea ecosystems around the world

Histopathological correlates of hemorrhagic lesions on ex vivo MRI in immunized Alzheimer’s disease cases.

Hemorrhagic Amyloid-Related Imaging Abnormalities (ARIA-H) on MRI are frequently observed adverse events in the context of amyloid β (Aβ) immunotherapy trials in patients with Alzheimer’s disease (AD). The underlying histopathology and pathophysiological mechanisms of ARIA-H remain largely unknown, although coexisting cerebral amyloid angiopathy (CAA) may play a key role. Here, we used ex vivo MRI in cases that underwent Aβ immunotherapy during life to screen for hemorrhagic lesions and assess underlying tissue and vascular alterations. We hypothesized that these lesions would be associated with severe CAA.Ten cases were selected from the long-term follow-up study of patients who enrolled in the first clinical trial of active Aβ immunization with AN1792 for AD (iAD cases). Eleven matched non-immunized AD cases from an independent brain brank were used as ‘controls’ (cAD cases). Formalin-fixed occipital brain slices were imaged at 7T MRI to screen for hemorrhagic lesions (i.e. microbleeds and cortical superficial siderosis). Samples with and without hemorrhagic lesions were cut and stained. AI-assisted quantification of Aβ plaque area, cortical and leptomeningeal CAA area, density of iron and calcium positive cells, and reactive astrocytes and activated microglia was performed.On ex vivo MRI, cortical superficial siderosis was observed in 5/10 iAD cases compared to 1/11 cAD cases (κ = 0.5). On histopathology, these areas revealed iron and calcium positive deposits in the cortex. Within the iAD group, areas with siderosis on MRI revealed greater leptomeningeal CAA and concentric splitting of the vessel walls compared to areas without siderosis. Moreover, greater density of iron positive cells in the cortex was associated with lower Aβ plaque area and a trend towards increased post-vaccination antibody titers. This work highlights the use of ex vivo MRI to investigate the neuropathological correlates of hemorrhagic lesions observed in the context of Aβ immunotherapy. These findings suggest a possible role for CAA in the formation of ARIA-H, awaiting confirmation in future studies that include brain tissue of patients who received passive immunotherapy against Aβ with available in vivo MRI during life

Histopathological correlates of haemorrhagic lesions on ex vivo magnetic resonance imaging in immunized Alzheimer's disease cases

Haemorrhagic amyloid-related imaging abnormalities on MRI are frequently observed adverse events in the context of amyloid β immunotherapy trials in patients with Alzheimer’s disease. The underlying histopathology and pathophysiological mechanisms of haemorrhagic amyloid-related imaging abnormalities remain largely unknown, although coexisting cerebral amyloid angiopathy may play a key role. Here, we used ex vivo MRI in cases that underwent amyloid β immunotherapy during life to screen for haemorrhagic lesions and assess underlying tissue and vascular alterations. We hypothesized that these lesions would be associated with severe cerebral amyloid angiopathy. Ten cases were selected from the long-term follow-up study of patients who enrolled in the first clinical trial of active amyloid β immunization with AN1792 for Alzheimer’s disease. Eleven matched non-immunized Alzheimer’s disease cases from an independent brain brank were used as ‘controls’. Formalin-fixed occipital brain slices were imaged at 7 T MRI to screen for haemorrhagic lesions (i.e. microbleeds and cortical superficial siderosis). Samples with and without haemorrhagic lesions were cut and stained. Artificial intelligence-assisted quantification of amyloid β plaque area, cortical and leptomeningeal cerebral amyloid angiopathy area, the density of iron and calcium positive cells and reactive astrocytes and activated microglia was performed. On ex vivo MRI, cortical superficial siderosis was observed in 5/10 immunized Alzheimer’s disease cases compared with 1/11 control Alzheimer’s disease cases (κ = 0.5). On histopathology, these areas revealed iron and calcium positive deposits in the cortex. Within the immunized Alzheimer’s disease group, areas with siderosis on MRI revealed greater leptomeningeal cerebral amyloid angiopathy and concentric splitting of the vessel walls compared with areas without siderosis. Moreover, greater density of iron-positive cells in the cortex was associated with lower amyloid β plaque area and a trend towards increased post-vaccination antibody titres. This work highlights the use of ex vivo MRI to investigate the neuropathological correlates of haemorrhagic lesions observed in the context of amyloid β immunotherapy. These findings suggest a possible role for cerebral amyloid angiopathy in the formation of haemorrhagic amyloid-related imaging abnormalities, awaiting confirmation in future studies that include brain tissue of patients who received passive immunotherapy against amyloid β with available in vivo MRI during life