Cerebral artery dilation during transient ischemia is impaired by amyloid β deposition around the cerebral artery in Alzheimer’s disease model mice

AbstractTransient ischemia is an exacerbation factor of Alzheimer’s disease (AD). We aimed to examine the influence of amyloid β (Aβ) deposition around the cerebral (pial) artery in terms of diameter changes in the cerebral artery during transient ischemia in AD model mice (APPNL-G-F) under urethane anesthesia. Cerebral vasculature and Aβ deposition were examined using two-photon microscopy. Cerebral ischemia was induced by transient occlusion of the unilateral common carotid artery. The diameter of the pial artery was quantitatively measured. In wild-type mice, the diameter of arteries increased during occlusion and returned to their basal diameter after re-opening. In AD model mice, the artery response during occlusion differed depending on Aβ deposition sites. Arterial diameter changes at non-Aβ deposition site were similar to those in wild-type mice, whereas they were significantly smaller at Aβ deposition site. The results suggest that cerebral artery changes during ischemia are impaired by Aβ deposition.

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A Novel Phospholipid Derivative of Indomethacin, DP-155 [Mixture of 1-Steroyl and 1-Palmitoyl-2-{6-[1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetamido]hexanoyl}-sn-glycero-3-phosophatidyl Choline], Shows Superior Safety and Similar Efficacy in Reducing Brain Amyloid β in an Alzheimer's Disease Model

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.106.103184 ◽

2006 ◽

Vol 318 (3) ◽

pp. 1248-1256 ◽

Cited By ~ 23

Author(s):

E. Dvir ◽

J. E. Friedman ◽

J. Y. Lee ◽

J. Y. Koh ◽

F. Younis ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Disease Model ◽

Amyloid Β ◽

Similar Efficacy

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Microglia-Based Sex-Biased Neuropathology in Early-Stage Alzheimer’s Disease Model Mice and the Potential Pharmacologic Efficacy of Dioscin

Cells ◽

10.3390/cells10113261 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3261

Author(s):

Xiao Liu ◽

Qian Zhou ◽

Jia-He Zhang ◽

Xiaoying Wang ◽

Xiumei Gao ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Stage ◽

Disease Model ◽

Amyloid Β ◽

Brain Lesions ◽

Synaptic Dysfunction ◽

Synaptic Loss ◽

And Function ◽

The Brain

Alzheimer’s disease (AD), the most common form of dementia, is characterized by amyloid-β (Aβ) accumulation, microglia-associated neuroinflammation, and synaptic loss. The detailed neuropathologic characteristics in early-stage AD, however, are largely unclear. We evaluated the pathologic brain alterations in young adult App knock-in model AppNL-G-F mice at 3 and 6 months of age, which corresponds to early-stage AD. At 3 months of age, microglia expression in the cortex and hippocampus was significantly decreased. By the age of 6 months, the number and function of the microglia increased, accompanied by progressive amyloid-β deposition, synaptic dysfunction, neuroinflammation, and dysregulation of β-catenin and NF-κB signaling pathways. The neuropathologic changes were more severe in female mice than in male mice. Oral administration of dioscin, a natural product, ameliorated the neuropathologic alterations in young AppNL-G-F mice. Our findings revealed microglia-based sex-differential neuropathologic changes in a mouse model of early-stage AD and therapeutic efficacy of dioscin on the brain lesions. Dioscin may represent a potential treatment for AD.

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A fragment of cell adhesion molecule L1 reduces amyloid-β plaques in a mouse model of Alzheimer’s disease

Cell Death and Disease ◽

10.1038/s41419-021-04348-6 ◽

2022 ◽

Vol 13 (1) ◽

Author(s):

Junkai Hu ◽

Stanley Li Lin ◽

Melitta Schachner

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cell Adhesion ◽

Adhesion Molecule ◽

Cell Adhesion Molecule ◽

Transforming Growth Factor ◽

Amyloid Β ◽

Wild Type ◽

Model Of Alzheimer’S Disease ◽

Cell Adhesion Molecule L1

AbstractDeposition of amyloid-β (Aβ) in the brain is one of the important histopathological features of Alzheimer’s disease (AD). Previously, we reported a correlation between cell adhesion molecule L1 (L1) expression and the occurrence of AD, but its relationship was unclear. Here, we report that the expression of L1 and a 70 kDa cleavage product of L1 (L1-70) was reduced in the hippocampus of AD (APPswe) mice. Interestingly, upregulation of L1-70 expression in the hippocampus of 18-month-old APPswe mice, by parabiosis involving the joining of the circulatory system of an 18-month-old APPswe mouse with a 2-month-old wild-type C57BL/6 mouse, reduced amyloid plaque deposition. Furthermore, the reduction was accompanied by the appearance of a high number of activated microglia. Mechanistically, we observed that L1-70 could combine with topoisomerase 1 (Top1) to form a complex, L1-70/Top1, that was able to regulate expression of macrophage migration inhibitory factor (MIF), resulting in the activation of microglia and reduction of Aβ plaques. Also, transforming growth factor β1 (TGFβ-1) transferred from the blood of young wild-type C57BL/6 mice to the aged AD mice, was identified as a circulating factor that induces full-length L1 and L1-70 expression. All together, these findings suggest that L1-70 contributes to the clearance of Aβ in AD, thereby adding a novel perspective in understanding AD pathogenesis.

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PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1606171113 ◽

2016 ◽

Vol 113 (43) ◽

pp. 12292-12297 ◽

Cited By ~ 46

Author(s):

Loukia Katsouri ◽

Yau M. Lim ◽

Katrin Blondrath ◽

Ioanna Eleftheriadou ◽

Laura Lombardero ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Pyramidal Neurons ◽

Lentiviral Vector ◽

Disease Model ◽

Amyloid Β ◽

Neuronal Loss ◽

Peroxisome Proliferator ◽

Neuroprotective Effects ◽

Peroxisome Proliferator Activated Receptor

Current therapies for Alzheimer’s disease (AD) are symptomatic and do not target the underlying Aβ pathology and other important hallmarks including neuronal loss. PPARγ-coactivator-1α (PGC-1α) is a cofactor for transcription factors including the peroxisome proliferator-activated receptor-γ (PPARγ), and it is involved in the regulation of metabolic genes, oxidative phosphorylation, and mitochondrial biogenesis. We previously reported that PGC-1α also regulates the transcription of β-APP cleaving enzyme (BACE1), the main enzyme involved in Aβ generation, and its expression is decreased in AD patients. We aimed to explore the potential therapeutic effect of PGC-1α by generating a lentiviral vector to express human PGC-1α and target it by stereotaxic delivery to hippocampus and cortex of APP23 transgenic mice at the preclinical stage of the disease. Four months after injection, APP23 mice treated with hPGC-1α showed improved spatial and recognition memory concomitant with a significant reduction in Aβ deposition, associated with a decrease in BACE1 expression. hPGC-1α overexpression attenuated the levels of proinflammatory cytokines and microglial activation. This effect was accompanied by a marked preservation of pyramidal neurons in the CA3 area and increased expression of neurotrophic factors. The neuroprotective effects were secondary to a reduction in Aβ pathology and neuroinflammation, because wild-type mice receiving the same treatment were unaffected. These results suggest that the selective induction of PGC-1α gene in specific areas of the brain is effective in targeting AD-related neurodegeneration and holds potential as therapeutic intervention for this disease.

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Self-Protecting Biomimetic Nanozyme for Selective and Synergistic Clearance of Peripheral Amyloid-β in an Alzheimer’s Disease Model

Journal of the American Chemical Society ◽

10.1021/jacs.0c08395 ◽

2020 ◽

Vol 142 (52) ◽

pp. 21702-21711

Author(s):

Mengmeng Ma ◽

Zhenqi Liu ◽

Nan Gao ◽

Zifeng Pi ◽

Xiubo Du ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Disease Model ◽

Amyloid Β

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Hybrid FMT–CT imaging of amyloid-β plaques in a murine Alzheimer's disease model

NeuroImage ◽

10.1016/j.neuroimage.2008.10.038 ◽

2009 ◽

Vol 44 (4) ◽

pp. 1304-1311 ◽

Cited By ~ 81

Author(s):

D HYDE ◽

R DEKLEINE ◽

S MACLAURIN ◽

E MILLER ◽

D BROOKS ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Disease Model ◽

Amyloid Β ◽

Ct Imaging

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Detection and Prediction of Mild Cognitive Impairment in Alzheimer’s Disease Mice

Journal of Alzheimer s Disease ◽

10.3233/jad-200675 ◽

2020 ◽

Vol 77 (3) ◽

pp. 1209-1221

Author(s):

Surya Prakash Rai ◽

Pablo Bascuñana ◽

Mirjam Brackhan ◽

Markus Krohn ◽

Luisa Möhle ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Cognitive Dysfunction ◽

Age Of Onset ◽

Amyloid Β ◽

Current Approach ◽

Classification Algorithm ◽

Wild Type

Background: The recent failure of clinical trials to treat Alzheimer’s disease (AD) indicates that the current approach of modifying disease is either wrong or is too late to be efficient. Mild cognitive impairment (MCI) denotes the phase between the preclinical phase and clinical overt dementia. AD mouse models that overexpress human amyloid-β (Aβ) are used to study disease pathogenesis and to conduct drug development/testing. However, there is no direct correlation between the Aβ deposition, the age of onset, and the severity of cognitive dysfunction. Objective: To detect and predict MCI when Aβ plaques start to appear in the hippocampus of an AD mouse. Methods: We trained wild-type and AD mice in a Morris water maze (WM) task with different inter-trial intervals (ITI) at 3 months of age and assessed their WM performance. Additionally, we used a classification algorithm to predict the genotype (APPtg versus wild-type) of an individual mouse from their respective WM data. Results: MCI can be empirically detected using a short-ITI protocol. We show that the ITI modulates the spatial learning of AD mice without affecting the formation of spatial memory. Finally, a simple classification algorithm such as logistic regression on WM data can give an accurate prediction of the cognitive dysfunction of a specific mouse. Conclusion: MCI can be detected as well as predicted simultaneously with the onset of Aβ deposition in the hippocampus in AD mouse model. The mild cognitive impairment prediction can be used for assessing the efficacy of a treatment.

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