Tatjana Nilsson

Neuropathology of the hippocampus in FTLD-Tau with Pick bodies: a study of the BrainNet Europe Consortium.

G. G. Kovacs, A. J. M. Rozemuller, J. C. van Swieten, E. Gelpi, K. Majtenyi, S. Al‐Sarraj, C. Troakes, I. Bódi, A. King, T. Hortobágyi, M. M. Esiri, O. Ansorge, G. Giaccone, I. Ferrer, T. Arzberger, N. Bogdanovic, T. Nilsson, I. Leisser, I. Alafuzoff, J. W. Ironside, H. Kretzschmar and H. Budka (2013) Neuropathology and Applied Neurobiology39, 166–178

Cognitive impairment in the Tg6590 transgenic rat model of Alzheimer’s disease

Recently, interest in the rat as an animal model of Alzheimer’s disease (AD) has been growing. We have previously described the Tg6590 transgenic rat line expressing the amyloid precursor protein containing the Swedish AD mutation (K670M/N671L) that shows early stages of Aβ deposition, predominantly in cerebrovascular blood vessels, after 15 months of age. Here we show that by the age of 9 months, that is long before the appearance of Aβ deposits, the Tg6590 rats exhibit deficits in the Morris water maze spatial navigation task and altered spontaneous behaviour in the open‐field test. The levels of soluble Aβ were elevated both in the hippocampus and cortex of transgenic animals. Magnetic resonance imaging showed no major changes in the brains of transgenic animals, although they tended to have enlarged lateral ventricles when compared to control animals. The Tg6590 transgenic rat line should prove a suitable model of early AD for advanced studies including serial cerebrospinal fluid sampling, electrophysiology, neuroimaging or complex behavioural testing.

Presenilin dependence of phospholipase C and protein kinase C signaling

Presenilins (PSs) are involved in processing several proteins such as the amyloid precursor protein (APP), as well as in pathways for cell death and survival. We previously showed that some familial Alzheimer’s disease PS mutations cause increased basal and acetylcholine muscarinic receptor‐stimulated phospholipase C (PLC) activity which was γ‐secretase dependent. To further evaluate the dependence of PLC on PSs we measured PLC activity and the activation of variant protein kinase C (PKC) isoforms in mouse embryonic fibroblasts (MEFs) lacking either PS1, PS2, or both. PLC activity and PKCα and PKCγ activations were significantly lower in PS1 and PS2 double knockout MEFs after PLC stimulation. Protein levels of PKCα and PKCγ were lower in PS1 and PS2 double knockout MEFs. In contrast, PKCδ levels were significantly elevated in PS1 and PS2 double knockout as well as in PS1 knockout MEFs. Also, PKCδ levels were lowered after transfection of PS1 into PS1 knockout or PS double knockout MEFs. Using APP knockout MEFs we showed that the expression of PKCα, but not the other PKC isoforms is partially dependent on APP and can be regulated by APP intracellular domain (AICD). These results show that PLC and PKC activations are modulated by PS and also that PSs differentially regulate the expression of PKC isoforms by both APP/AICD‐dependent and independent mechanisms.

Neuropathological assessments of the pathology in frontotemporal lobar degeneration with TDP43-positive inclusions: an inter-laboratory study by the BrainNet Europe consortium

The BrainNet Europe consortium assessed the reproducibility in the assignment of the type of frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein (TDP) 43 following current recommendations. The agreement rates were influenced by the immunohistochemical (IHC) method and by the classification strategy followed. p62-IHC staining yielded good uniform quality of stains, but the most reliable results were obtained implementing specific Abs directed against the hallmark protein TDP43. Both assessment of the type and the extent of lesions were influenced by the Abs and by the quality of stain. Assessment of the extent of the lesions yielded poor results repeatedly; thus, the extent of pathology should not be used in diagnostic consensus criteria. Whilst 31 neuropathologists typed 30 FTLD-TDP cases, inter-rater agreement ranged from 19 to 100 per cent, being highest when applying phosphorylated TDP43/IHC. The agreement was highest when designating Type C or Type A/B. In contrast, there was a poor agreement when attempting to separate Type A or Type B FTLD-TDP. In conclusion, we can expect that neuropathologist, independent of his/her familiarity with FTLD-TDP pathology, can identify a TDP43-positive FTLD case. The goal should be to state a Type (A, B, C, D) or a mixture of Types (A/B, A/C or B/C). Neuropathologists, other clinicians and researchers should be aware of the pitfalls whilst doing so. Agreement can be reached in an inter-laboratory setting regarding Type C cases with thick and long neurites, whereas the differentiation between Types A and B may be more troublesome.

Erratum to: Neuropathological assessments of the pathology in frontotemporal lobar degeneration with TDP43-positive inclusions: an inter-laboratory study by the BrainNet Europe consortium[Journal of Neural Transmission, (2015), DOI 10.1007/s00702-014-1304-1]

Irina Alafuzoff • Maria Pikkarainen • Manuela Neumann • Thomas Arzberger • Safa Al-Sarraj • Istvan Bodi • Nenad Bogdanovic • Orso Bugiani • Isidro Ferrer • Ellen Gelpi • Stephen Gentleman • Giorgio Giaccone • Manuel B. Graeber • Tibor Hortobagyi • Paul G. Ince • James W. Ironside • Nikolaos Kavantzas • Andrew King • Penelope Korkolopoulou • Gábor G. Kovács • David Meyronet • Camelia Monoranu • Tatjana Nilsson • Piero Parchi • Efstratios Patsouris • Tamas Revesz • Wolfgang Roggendorf • Annemieke Rozemuller • Danielle Seilhean • Nathalie Streichenberger • Dietmar R. Thal • Stephen B. Wharton • Hans Kretzschmar

Neuropathology of the hippocampus in FTLD-Tau with Pick bodies: a study of the BrainNet Europe Consortium: Hippocampus in Pick's disease

G. G. Kovacs, A. J. M. Rozemuller, J. C. van Swieten, E. Gelpi, K. Majtenyi, S. Al‐Sarraj, C. Troakes, I. Bódi, A. King, T. Hortobágyi, M. M. Esiri, O. Ansorge, G. Giaccone, I. Ferrer, T. Arzberger, N. Bogdanovic, T. Nilsson, I. Leisser, I. Alafuzoff, J. W. Ironside, H. Kretzschmar and H. Budka (2013) Neuropathology and Applied Neurobiology39, 166–178

Neuropathology of the hippocampus in FTLD-Tau with Pick bodies

G. G. Kovacs, A. J. M. Rozemuller, J. C. van Swieten, E. Gelpi, K. Majtenyi, S. Al‐Sarraj, C. Troakes, I. Bódi, A. King, T. Hortobágyi, M. M. Esiri, O. Ansorge, G. Giaccone, I. Ferrer, T. Arzberger, N. Bogdanovic, T. Nilsson, I. Leisser, I. Alafuzoff, J. W. Ironside, H. Kretzschmar and H. Budka (2013) Neuropathology and Applied Neurobiology39, 166–178