Long-Term Dabigatran Treatment Delays Alzheimer’s Disease Pathogenesis in the TgCRND8 Mouse Model

Background: Secreted amyloid precursor protein-alpha (sAPPα) can enhance memory and is neurotrophic and neuroprotective across a range of disease-associated insults, including amyloid-β toxicity. In a significant step toward validating sAPPα as a therapeutic for Alzheimer’s disease (AD), we demonstrated that long-term overexpression of human sAPPα (for 8 months) in a mouse model of amyloidosis (APP/PS1) could prevent the behavioral and electrophysiological deficits that develop in these mice. Objective: To explore the underlying molecular mechanisms responsible for the significant physiological and behavioral improvements observed in sAPPα-treated APP/PS1 mice. Methods: We assessed the long-term effects on the hippocampal transcriptome following continuous lentiviral delivery of sAPPα or empty-vector to male APP/PS1 mice and wild-type controls using Affymetrix Mouse Transcriptome Assays. Data analysis was carried out within the Affymetrix Transcriptome Analysis Console and an integrated analysis of the resulting transcriptomic data was performed with Ingenuity Pathway analysis (IPA). Results: Mouse transcriptome assays revealed expected AD-associated gene expression changes in empty-vector APP/PS1 mice, providing validation of the assays used for the analysis. By contrast, there were specific sAPPα-associated gene expression profiles which included increases in key neuroprotective genes such as Decorin, betaine-GABA transporter, and protocadherin beta-5, subsequently validated by qRT-PCR. An integrated biological pathways analysis highlighted regulation of GABA receptor signaling, cell survival, and inflammatory responses. Furthermore, upstream gene regulatory analysis implicated sAPPα activation of Interleukin-4, which can counteract inflammatory changes in AD. Conclusion: This study identified key molecular processes that likely underpin the long-term neuroprotective and therapeutic effects of increasing sAPPα levels in vivo

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Genetic Ablation of Apolipoprotein A-IV Accelerates Alzheimer's Disease Pathogenesis in a Mouse Model

American Journal Of Pathology ◽

10.1016/j.ajpath.2010.11.057 ◽

2011 ◽

Vol 178 (3) ◽

pp. 1298-1308 ◽

Cited By ~ 20

Author(s):

Yujie Cui ◽

Mingwei Huang ◽

Yingbo He ◽

Shuyan Zhang ◽

Yongzhang Luo

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Disease Pathogenesis ◽

Genetic Ablation ◽

Apolipoprotein A

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Prolonged Volatile Anesthetic Exposure Exacerbates Cognitive Impairment and Neuropathology in the 5xFAD Mouse Model of Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-210374 ◽

2021 ◽

pp. 1-12

Author(s):

Fanglei Han ◽

Jia Zhao ◽

Guoqing Zhao

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Volatile Anesthetics ◽

Model Of Alzheimer’S Disease ◽

Short Term Exposure ◽

5Xfad Mouse ◽

Anesthetic Exposure ◽

5Xfad Mice

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disease which shows a set of symptoms involving cognitive changes and psychological changes. Given that AD is the most common form of dementia in aging population and the increasing demand for anesthesia/surgery with aging, there has been significant interest in the exact impact of volatile anesthetics on cognitive function and pathological alterations in AD population. Objective: This study aimed to investigate behavioral changes and neuropathology in the 5xFAD mouse model of Alzheimer’s disease with short-term exposure or long-term exposure to desflurane, sevoflurane, or isoflurane. Methods: In this study, we exposed 5xFAD mouse model of AD to isoflurane, sevoflurane, or desflurane in two different time periods (30 min and 6 h), and the memory related behaviors as well as the pathological changes in 5xFAD mice were evaluated 7 days after the anesthetic exposure. Results: We found that short-term exposure to volatile anesthetics did not affect hippocampus dependent memory and the amyloid-β (Aβ) deposition in the brain. However, long-term exposure to sevoflurane or isoflurane significantly increased the Aβ deposition in CA1 and CA3 regions of hippocampus, as well as the glial cell activation in amygdala. Besides, the PSD-95 expression was decreased in 5xFAD mice with exposure to sevoflurane or isoflurane and the caspase-3 activation was enhanced in isoflurane, sevoflurane, and desflurane groups. Conclusion: Our results demonstrate the time-dependent effects of common volatile anesthetics and implicate that desflurane has the potential benefits to prolonged anesthetic exposure in AD patients.

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