| 1. |
- Bachiller, S., et al.
(author)
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Early-life stress elicits peripheral and brain immune activation differently in wild type and 5xFAD mice in a sex-specific manner
- 2022
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In: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 19
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Journal article (peer-reviewed)abstract
- BackgroundThe risk of developing Alzheimer’s disease (AD) is modulated by genetic and environmental factors. Early-life stress (ELS) exposure during critical periods of brain development can impact later brain function and health, including increasing the risk of developing AD. Microglial dysfunction and neuroinflammation have been implicated as playing a role in AD pathology and may be modulated by ELS. To complicate matters further, sex-specific effects have been noted in response to ELS and in the incidence and progression of AD.MethodsHere, we subjected male and female mice with either a wild type or 5xFAD familial AD-model background to maternal separation (MS) from postnatal day 2 to 14 to induce ELS.ResultsWe detected hippocampal neuroinflammatory alterations already at postnatal day 15. By 4 months of age, MS mice presented increased immobility time in the forced swim test and a lower discrimination index in the novel object recognition memory test compared to controls. We found altered Bdnf and Arc expression in the hippocampus and increased microglial activation in the prefrontal cortex due to MS in a sex-dependent manner. In 5xFAD mice specifically, MS exacerbated amyloid-beta deposition, particularly in females. In the periphery, the immune cell population was altered by MS exposure.ConclusionOverall, our results demonstrate that MS has both short- and long-term effects on brain regions related to memory and on the inflammatory system, both in the brain and periphery. These ELS-related effects that are detectable even in adulthood may exacerbate pathology and increase the risk of developing AD via sex-specific mechanisms.
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| 2. |
- Garcia, M.g., et al.
(author)
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Maternal separation differentially modulates early pathology by sex in 5xFAD Alzheimer’s disease-transgenic mice
- 2023
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In: Brain, Behavior, & Immunity - Health. - 2666-3546. ; 32
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Journal article (peer-reviewed)abstract
- Alzheimer’s disease (AD) is the most common neurodegenerative disease. Most cases of AD are considered idiopathic and likely due to a combination of genetic, environmental, and lifestyle-related risk factors. Despite occurring decades before the typical age of an AD diagnosis, early-life stress (ELS) has been suggested to have long-lasting effects that may contribute to AD risk and pathogenesis. Still, the mechanisms that underlie the role of ELS on AD risk remain largely unknown. Here, we used 5xFAD transgenic mice to study relatively short-term alterations related to ELS in an AD-like susceptible mouse model at 6 weeks of age. To model ELS, we separated pups from their dams for 3 h per day from postnatal day 2–14. Around 6 weeks of age, we found that maternally separated (MS) 5xFAD mice, particularly female mice, displayed increased amyloid-β-immunoreactivity in the anterior cingulate cortex (ACC) and basolateral amygdala (BLA). In anterior cingulate cortex, we also noted significantly increased intraneuronal amyloid-β-immunoreactivity associated with MS but only in female mice. Moreover, IBA1-positive DAPI density was significantly increased in relation to MS in ACC and BLA, and microglia in BLA of MS mice had significantly different morphology compared to microglia in non-MS 5xFAD mice. Cytokine analysis showed that male MS mice, specifically, had increased levels of neuroinflammatory markers CXCL1 and IL-10 in hippocampal extracts compared to non-MS counterparts. Additionally, hippocampal extracts from both male and female MS 5xFAD mice had decreased levels of synapse- and activity-related markers Bdnf, 5htr6, Cox2, and Syp in hippocampus. Lastly, we performed behavioral tests to evaluate anxiety- and depressive-like behavior and working memory but could not detect any significant differences between groups. Overall, we detected several sex-specific molecular and cellular alterations in 6-week-old adolescent 5xFAD mice associated with MS that may help explain the connection between ELS and AD risk.
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| 3. |
- Klementieva, O., et al.
(author)
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Nano-scale Infrared Imaging of β-sheet Structures in Synaptic Junctions of Primary Neurons Isolated from Transgenic Mice
- 2018
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In: 2018 43rd International Conference on Infrared Millimeter and Terahertz Waves, IRMMW-THz 2018. - 9781538638095 ; 2018-September
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Conference paper (peer-reviewed)abstract
- Aβ is a class of aggregation-prone proteins, which may misfold into stable, β-sheet rich fibrils. Aβ is linked to the development of synaptic pathology in Alzheimer's disease (AD). However, a main question in the AD field is how Aβ contributes to AD neuropathology? Up to now there is little evidence for protein structural changes in diseased neuron. Our aim is to study the distribution of β-sheet structures in AD transgenic neurons in order to uncover sub-cellular mechanism(s) by which amyloid β-sheet structures are involved in AD pathology.
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| 4. |
- Klementieva, O., et al.
(author)
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Pre-plaque conformational changes in Alzheimer's disease-linked Aβ and APP
- 2017
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Journal article (peer-reviewed)abstract
- Reducing levels of the aggregation-prone Aβ peptide that accumulates in the brain with Alzheimer's disease (AD) has been a major target of experimental therapies. An alternative approach may be to stabilize the physiological conformation of Aβ. To date, the physiological state of Aβ in brain remains unclear, since the available methods used to process brain tissue for determination of Aβ aggregate conformation can in themselves alter the structure and/or composition of the aggregates. Here, using synchrotron-based Fourier transform infrared micro-spectroscopy, non-denaturing gel electrophoresis and conformational specific antibodies we show that the physiological conformations of Aβ and amyloid precursor protein (APP) in brain of transgenic mouse models of AD are altered before formation of amyloid plaques. Furthermore, focal Aβ aggregates in brain that precede amyloid plaque formation localize to synaptic terminals. These changes in the states of Aβ and APP that occur prior to plaque formation may provide novel targets for AD therapy.
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| 5. |
- O. Freitas, Raul, et al.
(author)
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Nano-Infrared Imaging of Primary Neurons
- 2021
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In: Cells. - : MDPI AG. - 2073-4409. ; 10:10, s. 1-15
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Journal article (peer-reviewed)abstract
- Alzheimer’s disease (AD) accounts for about 70% of neurodegenerative diseases and is a cause of cognitive decline and death for one-third of seniors. AD is currently underdiagnosed, and it cannot be effectively prevented. Aggregation of amyloid-β (Aβ) proteins has been linked to the development of AD, and it has been established that, under pathological conditions, Aβ proteins undergo structural changes to form β-sheet structures that are considered neurotoxic. Numerous intensive in vitro studies have provided detailed information about amyloid polymorphs; however, little is known on how amyloid β-sheet-enriched aggregates can cause neurotoxicity in relevant settings. We used scattering-type scanning near-field optical microscopy (s-SNOM) to study amyloid structures at the nanoscale, in individual neurons. Specifically, we show that in well-validated systems, s-SNOM can detect amyloid β-sheet structures with nanometer spatial resolution in individual neurons. This is a proof-of-concept study to demonstrate that s-SNOM can be used to detect Aβ-sheet structures on cell surfaces at the nanoscale. Furthermore, this study is intended to raise neurobiologists’ awareness of the potential of s-SNOM as a tool for analyzing amyloid β-sheet structures at the nanoscale in neurons without the need for immunolabeling
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