| 1. |
- Jiang, RC, et al.
(författare)
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Autophagy Impairment in App Knock-in Alzheimer's Model Mice
- 2022
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Ingår i: Frontiers in aging neuroscience. - : Frontiers Media SA. - 1663-4365. ; 14, s. 878303-
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is characterized by impaired protein homeostasis leading to amyloid-β peptide (Aβ) amyloidosis. Amyloid precursor protein (APP) knock-in mice exhibit robust Aβ pathology, providing possibilities to determine its effect on protein homeostasis including autophagy. Here we compared human AD postmortem brain tissue with brains from two different types of App knock-in mice, AppNL–F and AppNL–G–F mice, exhibiting AD-like pathology. In AD postmortem brains, p62 levels are increased and p62-positive staining is detected in neurons, including potential axonal beadings, as well as in the vasculature and in corpora amylacea. Interestingly, p62 is also increased in the neurons in 12-month-old AppNL–G–F mice. In brain homogenates from 12-month-old AppNL–G–F mice, both p62 and light chain 3 (LC3)-II levels are increased as compared to wildtype (WT) mice, indicating inhibited autophagy. Double immunostaining for LC3 and Aβ revealed LC3-positive puncta in hippocampus of 24-month-old AppNL–F mice around the Aβ plaques which was subsequently identified by electron microscopy imaging as an accumulation of autophagic vacuoles in dystrophic neurites around the Aβ plaques. Taken together, autophagy is impaired in App knock-in mice upon increased Aβ pathology, indicating that App knock-in mouse models provide a platform for understanding the correlation between Aβ and autophagy.
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| 2. |
- Morcuende, A, et al.
(författare)
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Immunomodulatory Role of CB2 Receptors in Emotional and Cognitive Disorders
- 2022
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Ingår i: Frontiers in psychiatry. - : Frontiers Media SA. - 1664-0640. ; 13, s. 866052-
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Tidskriftsartikel (refereegranskat)abstract
- Emotional behavior, memory, and learning have been associated with alterations in the immune system in neuropsychiatric and neurodegenerative diseases. In recent years, several studies pointed out the involvement of the cannabinoid receptor 2 (CB2r) in the immune system and the regulation of inflammation. This receptor is widely distributed in different tissues and organs with higher expression in spleen and immune system cells. However, CB2r has also been detected in several brain areas and different brain cell types, such as neurons and glia. These findings suggest that CB2r may closely relate the immune system and the brain circuits regulating inflammation, mood, and cognitive functions. Therefore, we review the studies that may help elucidate the molecular bases of CB2r in regulating inflammation in different brain cells and its role in the pathophysiology of psychiatric and neurodegenerative disorders.
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| 3. |
- Pang, KL, et al.
(författare)
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An App knock-in rat model for Alzheimer's disease exhibiting Aβ and tau pathologies, neuronal death and cognitive impairments
- 2022
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Ingår i: Cell research. - : Springer Science and Business Media LLC. - 1748-7838 .- 1001-0602. ; 32:2, s. 157-175
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Tidskriftsartikel (refereegranskat)abstract
- A major obstacle in Alzheimer’s disease (AD) research is the lack of predictive and translatable animal models that reflect disease progression and drug efficacy. Transgenic mice overexpressing amyloid precursor protein (App) gene manifest non-physiological and ectopic expression of APP and its fragments in the brain, which is not observed in AD patients. The App knock-in mice circumvented some of these problems, but they do not exhibit tau pathology and neuronal death. We have generated a rat model, with three familiar App mutations and humanized Aβ sequence knocked into the rat App gene. Without altering the levels of full-length APP and other APP fragments, this model exhibits pathologies and disease progression resembling those in human patients: deposit of Aβ plaques in relevant brain regions, microglia activation and gliosis, progressive synaptic degeneration and AD-relevant cognitive deficits. Interestingly, we have observed tau pathology, neuronal apoptosis and necroptosis and brain atrophy, phenotypes rarely seen in other APP models. This App knock-in rat model may serve as a useful tool for AD research, identifying new drug targets and biomarkers, and testing therapeutics.
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