Near-infrared target enhanced peripheral clearance of amyloid-β in Alzheimer's disease model

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

The Journal of Physiological Sciences ◽

10.1186/s12576-020-00785-8 ◽

2020 ◽

Vol 70 (1) ◽

Author(s):

Nobuhiro Watanabe ◽

Yoshihiro Noda ◽

Taeko Nemoto ◽

Kaori Iimura ◽

Takahiko Shimizu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebral Artery ◽

Disease Model ◽

Amyloid Β ◽

Wild Type ◽

Transient Ischemia ◽

Basal Diameter ◽

Two Photon Microscopy ◽

Pial Artery

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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Monocytes in the Peripheral Clearance of Amyloid-β and Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-181177 ◽

2019 ◽

Vol 68 (4) ◽

pp. 1391-1400 ◽

Cited By ~ 1

Author(s):

Huifang Guo ◽

Zhaohua Zhao ◽

Ruisan Zhang ◽

Peng Chen ◽

Xiaohua Zhang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

Peripheral Clearance

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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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Relationship Between Peripheral Transport Proteins and Plasma Amyloid-β in Patients with Alzheimer’s Disease Were Different from Cognitively Normal Controls: A Propensity Score Matching Analysis

Journal of Alzheimer s Disease ◽

10.3233/jad-191320 ◽

2020 ◽

Vol 78 (2) ◽

pp. 699-709

Author(s):

Ling Gao ◽

Jin Wang ◽

Yu Jiang ◽

Shan Wei ◽

Suhang Shang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Propensity Score ◽

Propensity Score Matching ◽

Amyloid Β ◽

Transport Proteins ◽

Cognitively Normal ◽

Propensity Score Matching Analysis ◽

Soluble Rage ◽

Peripheral Clearance

Background: Transport proteins, soluble LRP1 (sLRP1) and soluble RAGE (sRAGE), play a pivotal role in the peripheral clearance of plasma amyloid-β (Aβ). However, their relationship is seldom discussed, especially in Alzheimer’s disease (AD). Objective: To explore whether their relationship in patients with AD varied from those in cognitively normal (CN) controls. Methods: We initially recruited 70 patients with AD and 725 CN controls, then applied propensity score matching (PSM) analysis to balance the differences between two groups. Plasma levels of sLRP1, sRAGE, and Aβ were measured using commercial ELISA kits and log transformed when skewed distributed. The relationship between sLRP1/sRAGE and plasma Aβ were analyzed using Pearson’s correlation analysis followed by multiple linear regression separately in the original population and matched participants. Results: After PSM, 70 patients with AD and 140 matched controls were included for further analysis. Log sLRP1 was positively correlated with plasma Aβ40 in matched CN controls (r = 0.222, p = 0.008) but not in patients with AD (r = 0.137, p = 0.260). After multivariable adjustment, Log sLRP1 remained significantly associated with plasma Aβ40 in the CN group (β= 7.347, p = 0.014) but not in the AD group (β= 10.409, p = 0.105). In contrast, Log sLRP1 was not correlated with plasma Aβ42 in patients with AD or CN controls, and Log sRAGE was consistently not associated with plasma Aβ40 or Aβ42 in either group. Conclusion: The significant correlation between sLRP1 and plasma Aβ40 present in CN controls was not found in patients with AD, suggesting that their relationship was different in AD. However, the specific mechanisms and its influence on cerebral amyloid burden require further validation.

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