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J Neurosci. 2019 Mar 14. pii: 2920-18. doi: 10.1523/JNEUROSCI.2920-18.2019. [Epub ahead of print]

Synaptopodin deficiency ameliorates symptoms in the 3xTg mouse model of Alzheimer's disease.

Author information

1
Department of Neurobiology, The Weizmann Institute, Rehovot, 76100 Israel.
2
Department of Veterinary Resources, The Weizmann Institute, Rehovot, 76100 Israel.
3
Department of Neurobiology, The Weizmann Institute, Rehovot, 76100 Israel menahem.segal@weizmann.ac.il.

Abstract

Disruption in calcium homeostasis is linked to several pathologies and is suggested to play a pivotal role in the cascade of events leading to Alzheimer disease (AD). Synaptopodin (SP) residing in dendritic spines has been associated with ryanodine receptor (RyR), such that spines lacking SP release less calcium from stores. In this work, we mated SPKO with 3xTg mice (3xTg/SPKO) to test the effect of SP deficiency in the AD mouse. We found that 6 Months old male 3xTg/SPKO mice restored normal spatial learning in the Barns-maze, LTP in hippocampal slices and expression levels of RyR in the hippocampus that were altered in the 3xTg mice. In addition, there was a marked reduction in 3xTg-associated p-tau, amyloid beta plaques and activated microglia, in 3xTg/SPKO male and female mice. These experiments indicate that a reduction in expression of SP ameliorates AD-associated phenotype in 3xTg mice.SIGNIFICANCE STATEMENTThis study strengthens the proposed role of calcium stores in development of AD-associated phenotype in the 3xTg mouse model, in that a genetic reduction of the functioning of ryanodine receptors using synaptopodin-knockout mice ameliorates AD symptoms at the behavioral, electrophysiological and morphological levels of analysis.

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