Homira Behbahani

Studies to understand the biological mechanisms of cell degeneration in Alzheimer disease (AD) and CADASIL, and the NGF as a potential treatment strategy

Research focus

Project I. The role of Omi/HtrA2 protease activity in Alzheimer’s disease

In Homira Behbahani’s group, we focused on OMI/HTRA2, a multifunctional serine protease, located in mitochondria. OMI/HTRA2 is involved in the degradation of aberrantly folded proteins during conditions of cellular stress such as endoplasmatic reticulum stress, heat shock and ischemia-reperfusion. OMI/HTRA2 has been implicated in the pathogenesis of several neurodegenerative disorders including Alzheimer disease (AD). Previously, we showed interplay between mitochondrial OMI/HTRA2 and γ-secretase complexes in AD. By another report via genetic, histological, and biochemical studies, we provided further support of an involvement of OMI/HTRA2 in the pathology of AD. Combined with these studies, we have verified the biological role of OMI/HTRA2 protease activity during stress conditions, and showing interplay between OMI/HTRA2 and vimentin which might affect mitochondrial distribution in neurons. Currently, we have initiated studies whether association of OMI/HTRA2 with the cholinergic system with the focus on how mitochondrial function is affected by intracellular cholinergic signaling.

Project II. CADASIL as a model system to study vascular diseases and dementia

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary disease resulting from mutations of the NOTCH3 gene. Histopathological findings suggest that there are a reduced number of VSMCs surrounding these thickened vessels, but the cause of such reduction is under investigation. In this project we want to investigate the mechanisms involved in VSMCs degeneration in CADASIL focused on autophagy and inflammation. Our results can be important for other blood vessel disorders whose degeneration of blood vessels is essential. By these studies we will reach to a better understanding of the pathogenesis of CADASIL which would improve the prognosis of CADASIL and patients with other cerebral small vessel diseases.

Project III. NGF, A promising therapeutic concept in Alzheimer Disease

AD is characterized by early degeneration of cholinergic neurons and decreased levels of nerve growth factor (NGF). Thus, increasing the NGF levels by for instance encapsulated cell bio-delivery (ECB) is a potential treatment strategy. In collaboration with Professor Maria Eriksdotter and Associate Professor Taher Darreh-Shori, we attempt to characterize the factors involved in cell survival and NGF-production in encapsulated-NGF biodelivery (EC-NGF) implants using different experimental systems and approaches based on a strong translational science. Furthermore, we attempt to characterize the effect of pathological molecules present in AD patient’s CSF on NGF-producing cells (contemplating their negative impact on clinical NGF-ECB therapy). In parallel, we want to examine the mechanisms involved in NGF-internalization, and downstream impact on cholinergic system. Once internalized, we want to examine how does NGF positively modulate cholinergic signaling and restore mitochondrial function in AD. The project aims to enhance NGF levels in the AD brain using ECB technique.

Group members

Senior researcher

Homira Behbahani

Phone: +46-(0)8-585 836 24
Organizational unit: Winblad
E-mail: Homira.Behbahani@ki.se

PhD student

Mahmod Panahi

Organizational unit: Division of Neurogeriatrics
E-mail: mahmod.panahi@ki.se


Sumonto Mitra

Organizational unit: Department of Neurobiology, Care Sciences and Society (NVS), H1
E-mail: sumonto.mitra@ki.se

Silvia Turchetto MSc-student

Winant Van Os MSc-student

Selected publications

Differences in proliferation rate between CADASIL and control vascular smooth muscle cells are related to increased TGFβ expression.
Panahi M, Yousefi Mesri N, Samuelsson E, Coupland K, Forsell C, Graff C, et al
J. Cell. Mol. Med. 2018 Jun;22(6):3016-3024

Inverse relationship between erythrocyte size and platelet reactivity in elderly.
Milovanovic M, Nilsson S, Winblad B, Jelic V, Behbahani H, Shahnaz T, et al
Platelets 2017 Mar;28(2):182-186

Association of Platelet Serotonin Levels in Alzheimer's Disease with Clinical and Cerebrospinal Fluid Markers.
Tajeddinn W, Fereshtehnejad S, Seed Ahmed M, Yoshitake T, Kehr J, Shahnaz T, et al
J. Alzheimers Dis. 2016 05;53(2):621-30

Perforin Promotes Amyloid Beta Internalisation in Neurons.
Lana E, Khanbolouki M, Degavre C, Samuelsson E, Åkesson E, Winblad B, et al
Mol. Neurobiol. 2017 03;54(2):874-887

Mitochondrial dysfunction in a transgenic mouse model expressing human amyloid precursor protein (APP) with the Arctic mutation.
Rönnbäck A, Pavlov P, Mansory M, Gonze P, Marlière N, Winblad B, et al
J. Neurochem. 2016 Feb;136(3):497-502

Stress Conditions Increase Vimentin Cleavage by Omi/HtrA2 Protease in Human Primary Neurons and Differentiated Neuroblastoma Cells.
Lucotte B, Tajhizi M, Alkhatib D, Samuelsson E, Wiehager B, Schedin-Weiss S, et al
Mol. Neurobiol. 2015 Dec;52(3):1077-1092

Regulated Extracellular Choline Acetyltransferase Activity- The Plausible Missing Link of the Distant Action of Acetylcholine in the Cholinergic Anti-Inflammatory Pathway.
Vijayaraghavan S, Karami A, Aeinehband S, Behbahani H, Grandien A, Nilsson B, et al
PLoS ONE 2013 ;8(6):e65936

Modulation of the endoplasmic reticulum-mitochondria interface in Alzheimer's disease and related models.
Hedskog L, Pinho C, Filadi R, Rönnbäck A, Hertwig L, Wiehager B, et al
Proc. Natl. Acad. Sci. U.S.A. 2013 May;110(19):7916-21

Amyloid precursor protein accumulates in aggresomes in response to proteasome inhibitor.
Dehvari N, Mahmud T, Persson J, Bengtsson T, Graff C, Winblad B, et al
Neurochem. Int. 2012 Apr;60(5):533-42

Experimental studies of mitochondrial function in CADASIL vascular smooth muscle cells.
Viitanen M, Sundström E, Baumann M, Poyhonen M, Tikka S, Behbahani H
Exp. Cell Res. 2013 Feb;319(3):134-43

Erlin-2 is associated with active γ-secretase in brain and affects amyloid β-peptide production.
Teranishi Y, Hur J, Gu G, Kihara T, Ishikawa T, Nishimura T, et al
Biochem. Biophys. Res. Commun. 2012 Aug;424(3):476-81

Amyloid precursor protein accumulates in aggresomes in response to proteasome inhibitor.
Dehvari N, Mahmud T, Persson J, Bengtsson T, Graff C, Winblad B, et al
Neurochem. Int. 2012 Apr;60(5):533-42

Altered enzymatic activity and allele frequency of OMI/HTRA2 in Alzheimer's disease.
Westerlund M, Behbahani H, Gellhaar S, Forsell C, Belin A, Anvret A, et al
FASEB J. 2011 Apr;25(4):1345-52

Mitochondrial γ-secretase participates in the metabolism of mitochondria-associated amyloid precursor protein.
Pavlov P, Wiehager B, Sakai J, Frykman S, Behbahani H, Winblad B, et al
FASEB J. 2011 Jan;25(1):78-88

Association of Omi/HtrA2 with γ-secretase in mitochondria.
Behbahani H, Pavlov P, Wiehager B, Nishimura T, Winblad B, Ankarcrona M
Neurochem. Int. 2010 Nov;57(6):668-75

CD147, a gamma-secretase associated protein is upregulated in Alzheimer's disease brain and its cellular trafficking is affected by presenilin-2.
Nahalkova J, Volkmann I, Aoki M, Winblad B, Bogdanovic N, Tjernberg L, et al
Neurochem. Int. 2010 Jan;56(1):67-76

Leukemia inhibitory factor inhibits HIV-1 replication and is upregulated in placentae from nontransmitting women.
Patterson B, Behbahani H, Kabat W, Sullivan Y, O'Gorman M, Landay A, et al
J. Clin. Invest. 2001 Feb;107(3):287-94