Alzheimer 2013 Jun-13

 

GRN variant rs5848 reduces plasma and brain levels of granulin in Alzheimer’s disease patients.

J Alzheimers Dis. 2013;33(1):23-7.

Kämäläinen A, Viswanathan J, Natunen T, Helisalmi S, Kauppinen T, Pikkarainen M, Pursiheimo JP, Alafuzoff I, Kivipelto M, Haapasalo A, Soininen H, Herukka SK, Hiltunen M.

Institute of Clinical Medicine – Neurology, University of Eastern Finland, Kuopio, Finland.

Abstract

Genetic variants in the granulin (GRN) gene have been shown to increase the risk of Alzheimer’s disease (AD). Here, we report that the A allele of rs5848 in GRN reduces plasma granulin levels in a dose-dependent manner in a clinically-defined AD sample cohort. Similarly, the mRNA levels of granulin were decreased with respect to A allele of rs5848 in the inferior temporal cortex of neuropathologically confirmed AD patients. Our findings suggest that the A allele of rs5848 is functionally relevant by reducing the expression of granulin.

PMID: 22890097

 

Additional information:

Genetic variants in the granulin (GRN) gene have been shown to increase the risk of Alzheimer’s disease (AD) in various cohorts. The SNP rs5848, located in the 3’-untranslated region of GRN, is of particular importance. The A allele of rs5848 enhances the binding of microRNA-659 to the granulin mRNA leading to reduced expression of the gene. Here, we report that the rs5848 A allele reduces plasma granulin levels in a dose-dependent manner in a clinically-defined AD sample cohort. Furthermore, the mRNA levels of granulin were decreased with respect to the A allele of rs5848 in the inferior temporal cortex of neuropathologically confirmed AD patients. Since granulins are crucial for neuronal survival, and are implicated in the inflammatory response, reduced granulin levels have been suggested to cause neurodegeneration. Our findings suggest that a dose-dependent reduction in the granulin levels in plasma and brain due to the A allele of rs5848 result in a functional change in GRN.

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