Susanne Frykman

Synaptic degeneration in Alzheimer Disease

Research focus

We are aiming to elucidate the mechanisms underlying synaptic degeneration and dysfunction in Alzheimer Disease (AD) with the ultimate goal to rescue synaptic function and thereby alleviate symptoms of AD

Synaptic degeneration and dysfunction are early events in AD pathogenesis and correlate well with cognitive decline. Rescuing of synaptic function is highly likely to alleviate symptoms but in order to develop such strategies, we need to learn more about the underlying mechanisms. Given the last years’ failure in translating promising animal research into clinical trials, we believe it is important to study what really happens in AD brain. We are currently pursuing two main project along this line:

1. Identification of proteins with altered levels in vulnerable synapses in AD brain

We have performed an unbiased proteomic study of the outer molecular layer (OML) of the dentate gyrus where the synapses of the highly vulnerable perforant pathway are located. The OML was dissected from post-mortem brain sections from 5 AD and 5 control cases using laser capture microdissection (LCM) and quantitative mass spectrometry was performed. We identified 67 proteins with significantly altered levels in AD brain. After further selection and validation of these proteins, we now aim to:

  • Study the effect of the candidate proteins on synaptic function
  • Study the effect of the candidate proteins on metabolism of the synaptotoxic amyloid β-peptide (Aβ)
  • Evaluate the candidate proteins as biomarkers

2. Investigation of processing of the amyloid precursor protein in different species and developmental stages

The synaptoxic Aβ is produced from its’ precursor protein APP by the sequential cleavage of β- and γ-secretase. However, several other proteases also cleave APP. In addition, both APP and Aβ have extensive post-translational modifications. Our preliminary results show that the processing of APP differs significantly between human and mouse brain and also between adult and embryonic human brain.

We are part of the European Training Network SyDAD (Synaptic Dysfunction in Alzheimer Disease). SyDAD is sponsored by Horizon2020 and has goal to train 15 PhD student at six sites in Europe and to perform a collaborative research program to reveal the mechanisms behind synaptic dysfunction in AD.

We are looking for a post-doc to join the group

We would also be happy to supervise master/bachelor students

Group members:

Senior researcher

Susanne Frykman

Phone: +46-(0)8-585 836 25
Organizational unit: Tjernberg
E-mail: Susanne.Frykman@ki.se

Graduate Student

Hazal Haytural

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

Selected publications

Monoamine oxidase B is elevated in Alzheimer disease neurons, is associated with γ-secretase and regulates neuronal amyloid β-peptide levels.
Schedin-Weiss S, Inoue M, Hromadkova L, Teranishi Y, Yamamoto N, Wiehager B, et al
Alzheimers Res Ther 2017 Aug;9(1):57

Maturation and processing of the amyloid precursor protein is regulated by the potassium/sodium hyperpolarization-activated cyclic nucleotide-gated ion channel 2 (HCN2).
Frykman S, Inoue M, Ikeda A, Teranishi Y, Kihara T, Lundgren J, et al
Biochem. Biophys. Res. Commun. 2017 01;483(1):352-358

ADAM10 and BACE1 are localized to synaptic vesicles.
Lundgren J, Ahmed S, Schedin-Weiss S, Gouras G, Winblad B, Tjernberg L, et al
J. Neurochem. 2015 Nov;135(3):606-15

Activity-independent release of the amyloid β-peptide from rat brain nerve terminals.
Lundgren J, Ahmed S, Winblad B, Gouras G, Tjernberg L, Frykman S
Neurosci. Lett. 2014 Apr;566():125-30

Identification of two novel synaptic γ-secretase associated proteins that affect amyloid β-peptide levels without altering Notch processing.
Frykman S, Teranishi Y, Hur J, Sandebring A, Yamamoto N, Ancarcrona M, et al
Neurochem. Int. 2012 Jul;61(1):108-18

Minor contribution of presenilin 2 for γ-secretase activity in mouse embryonic fibroblasts and adult mouse brain.
Frånberg J, Svensson A, Winblad B, Karlström H, Frykman S
Biochem. Biophys. Res. Commun. 2011 Jan;404(1):564-8

gamma-Secretase dependent production of intracellular domains is reduced in adult compared to embryonic rat brain membranes.
Frånberg J, Karlström H, Winblad B, Tjernberg L, Frykman S
PLoS ONE 2010 Mar;5(3):e9772

Synaptic and endosomal localization of active gamma-secretase in rat brain.
Frykman S, Hur J, Frånberg J, Aoki M, Winblad B, Nahalkova J, et al
PLoS ONE 2010 Jan;5(1):e8948

Dissertations

Jolanta Lundgren, 2018: Losing connections in Alzheimer disease : the amyloid precursor protein processing machinery at the synapse 

Jenny Frånberg, 2010: Studies on gamma-secretase activity and products.

Address

Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research
Novum, floor 5
SE-141 86 Stockholm
Sweden 

AlzheimerNeurobiologyNeurodegenerative diseases