SEPT8 modulates β-amyloidogenic processing of APP by affecting the sorting and accumulation of BACE1

J Cell Sci. 2016 Jun 1;129(11):2224-38. doi: 10.1242/jcs.185215.

Kaisa M A Kurkinen ¹, Mikael Marttinen ¹, Laura Turner ², Teemu Natunen ¹, Petra Mäkinen ¹, Fanni Haapalinna ³, Timo Sarajärvi ¹, Sami Gabbouj ¹, Mitja Kurki ⁴, Jussi Paananen ⁴, Anne M Koivisto ³, Tuomas Rauramaa ⁵, Ville Leinonen ⁴, Heikki Tanila ⁶, Hilkka Soininen ³, Fiona R Lucas ², Annakaisa Haapasalo ⁷, Mikko Hiltunen ⁸

Affiliations

1 Institute of Biomedicine, School of Medicine, University of Eastern Finland, 70211 Kuopio, Finland.
2 Eisai Ltd., Bernard Katz Building, University College London, London WC1E 6BT, UK.
3 Institute of Clinical Medicine - Neurology, School of Medicine, University of Eastern Finland and Department of Neurology, Kuopio University Hospital, 70211 Kuopio, Finland.
4 Institute of Clinical Medicine - Neurosurgery, School of Medicine, University of Eastern Finland and Neurosurgery of NeuroCenter, Kuopio University Hospital, 70211 Kuopio, Finland.
5 Institute of Clinical Medicine - Pathology, School of Medicine, University of Eastern Finland and Department of Pathology, Kuopio University Hospital, 70211 Kuopio, Finland.
6 Department of Neurobiology, A.I. Virtanen, Institute for Molecular Sciences, School of Medicine, University of Eastern Finland, 70211 Kuopio, Finland.
7 Institute of Clinical Medicine - Neurology, School of Medicine, University of Eastern Finland and Department of Neurology, Kuopio University Hospital, 70211 Kuopio, Finland Department of Neurobiology, A.I. Virtanen, Institute for Molecular Sciences, School of Medicine, University of Eastern Finland, 70211 Kuopio, Finland [email protected] [email protected].
8 Institute of Biomedicine, School of Medicine, University of Eastern Finland, 70211 Kuopio, Finland Institute of Clinical Medicine - Neurology, School of Medicine, University of Eastern Finland and Department of Neurology, Kuopio University Hospital, 70211 Kuopio, Finland [email protected] [email protected].

PMID: 27084579 DOI: 10.1242/jcs.185215

Abstract

Dysfunction and loss of synapses are early pathogenic events in Alzheimer's disease. A central step in the generation of toxic Amyloid-β (Aβ) Peptides is the cleavage of amyloid precursor protein (APP) by β-site APP-cleaving Enzyme (BACE1). Here, we have elucidated whether downregulation of septin (SEPT) protein family members, which are implicated in synaptic plasticity and vesicular trafficking, affects APP processing and Aβ generation. SEPT8 was found to reduce soluble APPβ and Aβ levels in neuronal cells through a post-translational mechanism leading to decreased levels of BACE1 protein. In the human temporal cortex, we identified alterations in the expression of specific SEPT8 transcript variants in a manner that correlated with Alzheimer's-disease-related neurofibrillary pathology. These changes were associated with altered β-secretase activity. We also discovered that the overexpression of a specific Alzheimer's-disease-associated SEPT8 transcript variant increased the levels of BACE1 and Aβ Peptides in neuronal cells. These changes were related to an increased half-life of BACE1 and the localization of BACE1 in recycling endosomes. These data suggest that SEPT8 modulates β-amyloidogenic processing of APP through a mechanism affecting the intracellular sorting and accumulation of BACE1.

Keywords

Alzheimer's disease; Amyloid precursor protein; Amyloid-β; BACE1; SEPT8.

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