A Novel Mechanism for Memory/Synaptic Dysfunction in Tauopathy.

Identification: Xu, Huaxi


Description

A Novel Mechanism for Memory/Synaptic Dysfunction in Tauopathy
 
Huaxi Xu1, Yingjun Zhao1, Xiaoguang Li1, Hao Sun1, Juan-Pina Crespo1, Eliezer Masliah2, Paul Fraser3, Timothy Huang1
1Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; 2Departments of Neuroscience and Pathology, University of California San Diego, La Jolla, CA 92093, USA; 3Tanz Centre for Research in Neurodegenerative Diseases, Department of Medical Biophysics and Medicine (Neurology), University of Toronto, Toronto, ON M5S 3H2, Canada.
 
Deficits in memory storage and retrieval represent a key dysfunctional element in cognitive decline associated with tauopathies such as Alzheimer's disease (AD), frontotemporal dementia with tau pathology (FTD-T) and progressive supranuclear palsy (PSP). Currently, it remains unclear how memory storage and extinction deficiencies manifest in tauopathy. An SNP (rs1768208 C/T) that has been identified as a risk factor in PSP, FTD-T and AD leads to increased levels of the proapoptotic caspase-3-activating protein, appoptosin. We found that appoptosin overexpression increased caspase-mediated tau cleavage, tau aggregation, and synaptic dysfunction. In addition, heterozygous appoptosin deletion results in reduced NMDA receptor-dependent LTD (long-term depression) in mouse brain; these mice show normal memory formation but slowed memory decay. Furthermore, reduced expression of appoptosin can antagonize Aβ-induced LTD enhancement. Given that dysregulation of synaptic plasticity such as enhanced LTD has been observed in tauopathies such as AD, together with the observation that appoptosin expression is upregulated in patients with tauopathy, our results suggest that appoptosin has a role in driving synaptic dysfunction in tauopathy.
 
Funding acknowledgements:
R01AG038710 from National Institute of Health, and The Tanz Family Funds

Credits

Credits: None available.

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