Lars Tjernberg Group
Pathogenic pathways in Alzheimer Disease
Our research focuses on elucidating, in molecular and subcellular detail, which pathways lead to Alzheimer disease (AD).
Pathologically, AD is characterized by amyloid plaques formed by the amyloid β-peptide (Aβ), intracellular tangles consisting of the tau protein, and loss of neurons and synapses. Several lines of evidence suggest that the polymerization of Aβ, eventually leading to the formation of plaques, is an early and critical step in the cascade of events leading to AD. Still, exactly how Aβ is generated from its precursor APP, how it is trafficked within the neuron and where the polymerization is initiated is not known.
By combining cutting edge technology such as super-resolution microscopy and genetic code expansion in neuronal cultures we are finding the answers to these crucial research questions. To increase our understanding of the effect of Aβ in vivo, we have undertaken proteomics approaches. To elucidate which pathogenic pathways that are affected early, we have used a novel knock-in mouse model that overexpresses the pathogenic 42 residues variant of Aβ (Aβ42). We have identified differently expressed proteins at different time points, and concluded that certain pathways are activated already at 3month of age in hippocampus and cortex. Interestingly, other pathways are activated as the mice ages.
To find specific pathways involved in hippocampal synapse loss, we are using laser microdissection of human brain autopsies and mass spectrometry, and have found a high number of proteins that are dysregulated in AD, some of which could potentially be targeted for pharmaceutical intervention.
To successfully treat AD, it is seems necessary to start treatment at a pre-symptomatic stage. To this end we have used glycomics and found a set of glycans that discriminates between controls and pre-AD stages of disease. Based on these data we are now developing assays that hopefully will be of clinical use for pre-symptomatic detection of AD.
Lenka Hromadkova, visiting PhD student
Michael Axenhus, medical student
Tansu Bilge Köse, visiting undergraduate student
Selected scientific publications
Neuronal Aβ42 is enriched in small vesicles at the presynaptic side of synapses.
Yu Y, Jans DC, Winblad B, Tjernberg LO, Schedin-Weiss S
Life Sci Alliance 2018 Jun;1(3):e201800028
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 NG, Wiehager B, et al
Alzheimers Res Ther 2017 Aug;9(1):57
Super-resolution microscopy reveals γ-secretase at both sides of the neuronal synapse.
Schedin-Weiss S, Caesar I, Winblad B, Blom H, Tjernberg LO
Acta Neuropathol Commun 2016 Mar;4():29
ADAM10 and BACE1 are localized to synaptic vesicles.
Lundgren JL, Ahmed S, Schedin-Weiss S, Gouras GK, Winblad B, Tjernberg LO, et al
J Neurochem 2015 Nov;135(3):606-15
Loss of neprilysin alters protein expression in the brain of Alzheimer's disease model mice.
Nilsson P, Loganathan K, Sekiguchi M, Winblad B, Iwata N, Saido TC, et al
Proteomics 2015 Oct;15(19):3349-55
Activity-independent release of the amyloid β-peptide from rat brain nerve terminals.
Lundgren JL, Ahmed S, Winblad B, Gouras GK, Tjernberg LO, Frykman S
Neurosci Lett 2014 Apr;566():125-30
Analysis of microdissected neurons by 18O mass spectrometry reveals altered protein expression in Alzheimer's disease.
Hashimoto M, Bogdanovic N, Nakagawa H, Volkmann I, Aoki M, Winblad B, et al
J Cell Mol Med 2012 Aug;16(8):1686-700
Analysis of microdissected human neurons by a sensitive ELISA reveals a correlation between elevated intracellular concentrations of Abeta42 and Alzheimer's disease neuropathology.
Hashimoto M, Bogdanovic N, Volkmann I, Aoki M, Winblad B, Tjernberg LO
Acta Neuropathol 2010 May;119(5):543-54
Jolanta Lundgren, 2018: Losing connections in Alzheimer disease: the amyloid precursor protein processing machinery at the synapse
Yasuhiro Teranishi, 2012, Identification and investigation of gamma-secretase associated proteins from brain
Ji-Yeun Hur, 2010: The Alzheimer’s disease related gamma-secretase complex: Localization and novel interacting proteins
Jenny Frånberg, 2010: Studies on gamma-secretase activity and products
Hedvig Welander, 2010: Alzheimer disease: Studies on Abeta and gamma-secretase in human brain
Linda Söderberg, 2005: Characterization of the Alzheimer's disease-associated clac protein
Niklas Bark, 2004: Biophysical studies on aggregation processes and amyloid fibrils with focus on Alzheimer's disease