Role of microglial C5aR1 in the Arctic Alzheimer's Disease mouse model

Abstract Alzheimer’s disease (AD) is a progressive and degenerative brain disease and age is one of its strongest risk factors. Aging is a complex process but it is reasonable that a delayed aging process may lower the risk of AD or postpone its pathogenesis. Studies in C. elegans revealed that the activity of DAF-16 is required for the life span extension in many long-lived strains. The mammalian homologs for DAF-16 are the Forkhead box O (FOXO) transcription factors. FOXO3, one of the members in the FOXO family, has been identified in several studies as a susceptibility gene for human longevity. I found that the expression level of Foxo3 in the mouse brain decreases with age or in an AD mouse model. To further study the role of Foxo3 in AD, I generated Foxo3 conditional knockout mice which depletes Foxo3 in neural cells. These mice have reactive astrogliosis in the cortex and also upregulation of some astrocytes specific markers like Gfap and Aqp4. In vitro culture of primary astrocytes from the knockout mice shows impaired respiratory capacity in the Seahorse mito stress test, which corresponds to the expression level change of metabolic genes like Acot1. When we bred the knockout mice with 5xFAD, a mouse model for amyloid pathology. I found increased plaque load and core plaque size in the cortex of the mice with Foxo3 deficiency. This study shows the critical function of FOXO3 in maintaining brain homeostasis and provide new insights into AD pathogenesis and drug discovery.

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Role of Lipocalin-2 in Amyloid-Beta Oligomer-Induced Mouse Model of Alzheimer’s Disease

Antioxidants ◽

10.3390/antiox10111657 ◽

2021 ◽

Vol 10 (11) ◽

pp. 1657

Author(s):

Heeyoung Kang ◽

Hyun Joo Shin ◽

Hyeong Seok An ◽

Zhen Jin ◽

Jong Youl Lee ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Amyloid Beta ◽

Brain Injuries ◽

Lipocalin 2 ◽

Amyloid Toxicity ◽

Blood Brain Barrier Disruption ◽

Model Of Alzheimer’S Disease

Lipocalin-2 (LCN2) is an inflammatory protein with diverse functions in the brain. Although many studies have investigated the mechanism of LCN2 in brain injuries, the effect of LCN2 on amyloid-toxicity-related memory deficits in a mouse model of Alzheimer’s disease (AD) has been less studied. We investigated the role of LCN2 in human AD patients using a mouse model of AD. We created an AD mouse model by injecting amyloid-beta oligomer (AβO) into the hippocampus. In this model, animals exhibited impaired learning and memory. We found LCN2 upregulation in the human brain frontal lobe, as well as a positive correlation between white matter ischemic changes and serum LCN2. We also found increased astrocytic LCN2, microglia activation, iron accumulation, and blood–brain barrier disruption in AβO-treated hippocampi. These findings suggest that LCN2 is involved in a variety of amyloid toxicity mechanisms, especially neuroinflammation and oxidative stress.

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Faculty Opinions recommendation of New role of P2X7 receptor in an Alzheimer's disease mouse model.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.733499085.793549485 ◽

2018 ◽

Author(s):

Francesco Di Virgilio

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

P2x7 Receptor

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