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The Involvement of Canonical Wnt Signaling in Memory Impairment Induced by Chronic Cerebral Hypoperfusion in Mice

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Abstract

Chronic cerebral hypoperfusion (CCH) has been proposed to contribute to the progression of memory loss, which is the main symptom of vascular cognitive impairment (VCI). Accumulating evidence indicates that underlying pathophysiology, such as neurodegeneration, may lead to memory loss. However, the underlying molecular basis of memory loss in CCH remains unclear. Here, we investigated the roles of canonical Wnt signaling, which modulates hippocampal function, in a CCH model. CCH was induced by unilateral common carotid artery occlusion (UCCAO). Mice were randomly divided into a sham-operated group or one of three UCCAO groups with different endpoints (1.5, 2.5, and 3.5 months) after UCCAO. Memory function and hippocampal levels of Wnt-related proteins were measured. A Wnt activator, lithium, was administered intraperitoneally to assess memory improvements. In the groups examined 2.5 and 3.5 months after UCCAO, impaired object recognition memory was accompanied by inhibition of Wnt signaling and decreased expression of synaptic/neural activity-related proteins. Recognition memory and Wnt signaling were significantly positive correlated. Moreover, activation of Wnt signaling with lithium significantly attenuated memory loss and recovered synaptic/neural marker expression after UCCAO. Our results suggest that CCH may affect synaptic plasticity via dysregulation of signaling pathways, including canonical Wnt signaling, which could be partly involved in memory loss. As Wnt activator administration alleviated the effects of CCH on memory loss, modulation of Wnt signaling may be a promising therapeutic strategy for VCI.

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Abbreviations

αCAMKII:

α-Calcium-calmodulin-dependent kinase II

CA:

Cornus ammonis

CCH:

Chronic cerebral hypoperfusion

DG:

Dentate gyrus

DKK-1:

Dickkopf-1

GLUT:

Glucose transporter

GSK3β:

Glycogen synthase kinase 3β

IEGs:

Immediately early genes

NOR:

Novel object recognition

PSD95:

Postsynaptic density-95

UCCAO:

Unilateral common carotid artery occlusion

VCI:

Vascular cognitive impairment

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Funding

This work was financially supported by grants from the National Research Council of Science and Technology (NST) by the Korean government (MSIP) (CRC-15-04-KIST, G17290, G18230, K18850, and KSN1621850).

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Authors and Affiliations

  1. Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, 34054, South Korea

    Min-Soo Kim, Jihye Bang & Won Kyung Jeon

  2. Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, 02792, South Korea

    Min-Soo Kim, Jihye Bang & Won Kyung Jeon

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  1. Min-Soo Kim
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Correspondence to Won Kyung Jeon.

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All experiments were approved by the institutional animal care and use committee of Korea Institute of Science and Technology (Permit number: 2017-103), in concordance with the NIH and ARRIVE guidelines.

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Kim, MS., Bang, J. & Jeon, W.K. The Involvement of Canonical Wnt Signaling in Memory Impairment Induced by Chronic Cerebral Hypoperfusion in Mice. Transl. Stroke Res. 11, 734–746 (2020). https://doi.org/10.1007/s12975-019-00748-1

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