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
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 Science Alliance, June 2018, accepted
Monoamine oxidase B is elevated in Alzheimer disease neurons, is associated with γ-secretase and regulates neuronal amyloid β-peptide levels.
Alzheimers Res Ther 2017 Aug;9(1):57
Super-resolution microscopy reveals γ-secretase at both sides of the neuronal synapse.
Acta Neuropathol Commun 2016 Mar;4():29
ADAM10 and BACE1 are localized to synaptic vesicles.
J. Neurochem. 2015 Nov;135(3):606-15
Loss of neprilysin alters protein expression in the brain of Alzheimer's disease model mice.
Proteomics 2015 Oct;15(19):3349-55
Activity-independent release of the amyloid β-peptide from rat brain nerve terminals.
Neurosci. Lett. 2014 Apr;566():125-30
Analysis of microdissected neurons by 18O mass spectrometry reveals altered protein expression in Alzheimer's disease.
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.
Acta Neuropathol. 2010 May;119(5):543-54