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Somatostatin Maintains Permeability and Integrity of Blood-Brain Barrier in β-Amyloid Induced Toxicity

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Abstract

In Alzheimer’s disease (AD), the impaired clearance of β-amyloid peptide (Aβ) due to disrupted tight junction and transporter proteins is the prominent cause of disease progression. Somatostatin (SST) blocks the aggregation of Aβ and inflammation whereas reduction of SST levels in the CSF and brain tissue is associated with impaired cognitive function and memory loss. However, the role of SST in preservation of blood-brain barrier (BBB) integrity and functionality in Aβ-induced toxicity is not known. In the present study using human CMEC/D3 cells, we demonstrate that SST prevents Aβ-induced BBB permeability by regulating LRP1 and RAGE expression and improving the disrupted tight junction proteins. Furthermore, SST abrogates Aβ-induced JNK phosphorylation and expression of MMP2. Taken together, results presented here suggest that SST might serve as a therapeutic intervention in AD via targeting multiple pathways responsible for neurotoxicity, impaired BBB function, and disease progression.

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Abbreviations

AD:

Alzheimer’s disease

Aβ:

β-amyloid peptide

BBB:

Blood-brain barrier

hCMEC/D3:

Human cerebral microvascular endothelial cell line

CNS:

Central nervous system

ECM:

Extracellular matrix

FAM:

Fluorescein amidite

IFN-γ:

Interferon-γ

IL-1β:

Interleukin 1β

JNK:

c-Jun N-terminal kinases

ko :

Knock out

LPS:

Lipopolysaccharide

LRP:

Lipoprotein receptor-related protein

MMP:

Matrix metallopeptides

RAGE:

Receptor for advanced glycation end products

SST:

Somatostatin

SSTR:

Somatostatin receptor

tg :

Transgenic

TJP:

Tight junction protein

TNF-α:

Tumor necrosis factor-α

ZO:

Zonula occluden

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Acknowledgements

This work was funded by grants from Canadian Institute of Health Research (MOP 74465) and NSERC (402594-11, 16-05171) Canada to UK. SP is the recipient of CIHR Doctoral Fellowship. FACS study was aided by UBCFlow.

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  1. Faculty of Pharmaceutical Sciences, The University of British Columbia, V6T1Z3, Vancouver, BC, Canada

    Seungil Paik, Rishi K. Somvanshi & Ujendra Kumar

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This manuscript was written by SP and UK. Immunofluorescence colocalization, biochemical studies were done by SP and Western blot in part was done by RKS.

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Correspondence to Ujendra Kumar.

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Paik, S., Somvanshi, R.K. & Kumar, U. Somatostatin Maintains Permeability and Integrity of Blood-Brain Barrier in β-Amyloid Induced Toxicity. Mol Neurobiol 56, 292–306 (2019). https://doi.org/10.1007/s12035-018-1045-5

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