Lars Nilsson

• Phan, Tuan Anh; Palm, Pia; Stiphout, Anita van Haaren-van; Graav, Gretchen de; Lea, Marianne & Wøien, Hilde [Show all 12 contributors for this article] (2026). Serious gaming as a platform for interprofessional education about the medication process: A curricular resource for students of medicine, pharmacy, and nursing. Journal of Interprofessional Education & Practice. 45, p. 1–6. doi: 10.1016/j.xjep.2026.100846. Full text in Research Archive
• Vega, María Pagnon de la; Syvänen, Stina; Giedraitis, Vilmantas; Hooley, Monique; Konstantinidis, Evangelos & Meier, Silvio R. [Show all 16 contributors for this article] (2024). Altered amyloid-β structure markedly reduces gliosis in the brain of mice harboring the Uppsala APP deletion. Acta neuropathologica communications. 12:22(1), p. 1–16. doi: 10.1186/s40478-024-01734-x. Full text in Research Archive Show summary

  Deposition of amyloid beta (Aβ) into plaques is a major hallmark of Alzheimer’s disease (AD). Different amyloid precursor protein (APP) mutations cause early-onset AD by altering the production or aggregation properties of Aβ. We recently identified the Uppsala APP mutation (APPUpp), which causes Aβ pathology by a triple mechanism: increased β-secretase and altered α-secretase APP cleavage, leading to increased formation of a unique Aβ conformer that rapidly aggregates and deposits in the brain. The aim of this study was to further explore the effects of APPUpp in a transgenic mouse model (tg-UppSwe), expressing human APP with the APPUpp mutation together with the APPSwe mutation. Aβ pathology was studied in tg-UppSwe brains at different ages, using ELISA and immunohistochemistry. In vivo PET imaging with three different PET radioligands was conducted in aged tg-UppSwe mice and two other mouse models; tg-ArcSwe and tg-Swe. Finally, glial responses to Aβ pathology were studied in cell culture models and mouse brain tissue, using ELISA and immunohistochemistry. Tg-UppSwe mice displayed increased β-secretase cleavage and suppressed α-secretase cleavage, resulting in AβUpp42 dominated diffuse plaque pathology appearing from the age of 5–6 months. The γ-secretase cleavage was not affected. Contrary to tg-ArcSwe and tg-Swe mice, tg-UppSwe mice were [11C]PiB-PET negative. Antibody-based PET with the 3D6 ligand visualized Aβ pathology in all models, whereas the Aβ protofibril selective mAb158 ligand did not give any signals in tg-UppSwe mice. Moreover, unlike the other two models, tg-UppSwe mice displayed a very faint glial response to the Aβ pathology. The tg-UppSwe mouse model thus recapitulates several pathological features of the Uppsala APP mutation carriers. The presumed unique structural features of AβUpp42 aggregates were found to affect their interaction with anti-Aβ antibodies and profoundly modify the Aβ-mediated glial response, which may be important aspects to consider for further development of AD therapies.

• Sulheim, Einar; Widerøe, Marius; Bäck, Marcus; Nilsson, K Peter R; Hammarström, Per & Nilsson, Lars [Show all 8 contributors for this article] (2023). Contrast Enhanced Magnetic Resonance Imaging of Amyloid-β Plaques in a Murine Alzheimer's Disease Model. Journal of Alzheimer's Disease. ISSN 1387-2877. 93(2), p. 411–419. doi: 10.3233/JAD-220198. Full text in Research Archive Show summary

  Background: Early detection of amyloid-β (Aβ) aggregates is a critical step to improve the treatment of Alzheimer’s disease (AD) because neuronal damage by the Aβ aggregates occurs before clinical symptoms are apparent. We have previously shown that luminescent conjugated oligothiophenes (LCOs), which are highly specific towards protein aggregates of Aβ, can be used to fluorescently label amyloid plaque in living rodents. Objective: We hypothesize that the LCO can be used to target gadolinium to the amyloid plaque and hence make the plaque detectable by T1-weighted magnetic resonance imaging (MRI). Methods: A novel LCO-gadolinium construct was synthesized to selectively bind to Aβ plaques and give contrast in conventional T1-weighted MR images after intravenous injection in Tg-APPSwe mice. Results: We found that mice with high plaque-burden could be identified using the LCO-Gd constructs by conventional MRI. Conclusion: Our study shows that MR imaging of amyloid plaques is challenging but feasible, and hence contrast-mediated MR imaging could be a valuable tool for early AD detection.

• Zielinski, Mara; Reyes, Fernanda S. Peralta; Gremer, Lothar; Schemmert, Sarah; Frieg, Benedikt & Schäfer, Luisa U. [Show all 15 contributors for this article] (2023). Cryo-EM of Aβ fibrils from mouse models find tg-APP<inf>ArcSwe</inf> fibrils resemble those found in patients with sporadic Alzheimer’s disease. Nature Neuroscience. ISSN 1097-6256. 26, p. 2073–2080. doi: 10.1038/s41593-023-01484-4. Full text in Research Archive Show summary

  Abstract The use of transgenic mice displaying amyloid-β (Aβ) brain pathology has been essential for the preclinical assessment of new treatment strategies for Alzheimer’s disease. However, the properties of Aβ in such mice have not been systematically compared to Aβ in the brains of patients with Alzheimer’s disease. Here, we determined the structures of nine ex vivo Aβ fibrils from six different mouse models by cryogenic-electron microscopy. We found novel Aβ fibril structures in the APP/PS1, ARTE10 and tg-SwDI models, whereas the human type II filament fold was found in the ARTE10, tg-APP Swe and APP23 models. The tg-APP ArcSwe mice showed an Aβ fibril whose structure resembles the human type I filament found in patients with sporadic Alzheimer’s disease. A detailed assessment of the Aβ fibril structure is key to the selection of adequate mouse models for the preclinical development of novel plaque-targeting therapeutics and positron emission tomography imaging tracers in Alzheimer’s disease.

• Åbjørsbråten, Knut Sindre; Skaaraas, Gry Helen Enger Syverstad; Cunen, Celine Marie Løken; Bjørnstad, Daniel Marelius; Binder, Kristin Maria Gullestad & Bojarskaite, Laura [Show all 15 contributors for this article] (2022). Impaired astrocytic Ca2+ signaling in awake-behaving Alzheimer’s disease transgenic mice. eLIFE. doi: 10.7554/eLife.75055. Full text in Research Archive Show summary

  Increased astrocytic Ca2+ signaling has been shown in Alzheimer’s disease mouse models, but to date no reports have characterized behaviorally induced astrocytic Ca2+ signaling in such mice. Here, we employ an event-based algorithm to assess astrocytic Ca2+ signals in the neocortex of awake-behaving tg-ArcSwe mice and non-transgenic wildtype littermates while monitoring pupil responses and behavior. We demonstrate an attenuated astrocytic Ca2+ response to locomotion and an uncoupling of pupil responses and astrocytic Ca2+ signaling in 15-month-old plaque-bearing mice. Using the genetically encoded fluorescent norepinephrine sensor GRABNE, we demonstrate a reduced norepinephrine signaling during spontaneous running and startle responses in the transgenic mice, providing a possible mechanistic underpinning of the observed reduced astrocytic Ca2+ responses. Our data points to a dysfunction in the norepinephrine–astrocyte Ca2+ activity axis, which may account for some of the cognitive deficits observed in Alzheimer’s disease.

• Vega, María Pagnon De la; Giedraitis, Vilmantas; Michno, Wojciech; Kilander, Lena; Güner, Gökhan & Zielinski, Mara [Show all 21 contributors for this article] (2021). The Uppsala APP deletion causes early onset autosomal dominant Alzheimer's disease by altering APP processing and increasing amyloid β fibril formation. Science Translational Medicine. ISSN 1946-6234. 13:eabc6184(606), p. 1–13. doi: 10.1126/scitranslmed.abc6184. Full text in Research Archive Show summary

  Point mutations in the amyloid precursor protein gene (APP) cause familial Alzheimer’s disease (AD) by increasing generation or altering conformation of amyloid β (Aβ). Here, we describe the Uppsala APP mutation (Δ690–695), the first reported deletion causing autosomal dominant AD. Affected individuals have an age at symptom onset in their early forties and suffer from a rapidly progressing disease course. Symptoms and biomarkers are typical of sporadic AD, except that these three patients had high cerebrospinal fluid (CSF) Aβ42 and only modest brain pathology as detected by amyloid-positron emission tomography. Mass spectrometry and Western blot analyses of patient CSF and media from experimental cell cultures indicate that the Uppsala APP mutation alters APP processing by increasing β-secretase cleavage and affecting α-secretase cleavage. Furthermore, in vitro aggregation studies and analyses of patient brain tissue samples indicate that the longer form of mutated Aβ, AβUpp1–42Δ19–24, accelerates the formation of fibrils with unique polymorphs and their deposition into amyloid plaques in the affected brain.

• Edwin, Trine Holt; Henjum, Kristi; Nilsson, Lars; Watne, Leiv; Persson, Karin Ester Torun & Eldholm, Rannveig Sakshaug [Show all 12 contributors for this article] (2020). A high cerebrospinal fluid soluble TREM2 level is associated with slow clinical progression of Alzheimer's disease. Alzheimer's & Dementia. ISSN 1552-5260. 12(1). doi: 10.1002/dad2.12128. Full text in Research Archive Show summary

  Introduction: The progression rate of Alzheimer's disease (AD) varies and might be affected by the triggering receptor expressed on myeloid cells (TREM2) activity. We explored if cerebrospinal fluid (CSF) soluble TREM2 (sTREM2), a proxy of microglial activity, is associated with clinical progression rate. Methods: Patients with clinical AD (N = 231) were followed for up to 3 years after diagnosis. Cognitively healthy controls (N = 42) were followed for 5 years. CSF sTREM2 was analyzed by enzyme-linked immunosorbent assay. Group-based trajectory modeling revealed distinct clinical progression groups. Results: Higher CSF sTREM2 was associated with slow clinical progression. The slow- and medium-progressing groups had higher CSF sTREM2 than the cognitively healthy, who had a similar level to patients with rapid clinical progression. Discussion: CSF sTREM2 levels were associated with clinical progression in AD, regardless of core biomarkers. This could be useful in assessing disease development in relation to patient care and clinical trial recruitment. Keywords: Alzheimer's disease; Clinical Dementia Rating scale; disease progression; soluble triggering receptor expressed on myeloid cells 2 (sTREM2); trajectories.

• Henjum, Kristi; Årskog, Vibeke Helen; Jendresen, Charlotte Bille; Fladby, Tormod; Torp, Reidun & Nilsson, Lars (2020). Analyzing microglial-associated Aβ in Alzheimer’s disease transgenic mice with a novel mid-domain Aβ-antibody. Scientific Reports. 10(10590). doi: 10.1038/s41598-020-67419-2. Full text in Research Archive Show summary

  The mechanisms of amyloid-β (Aβ)-degradation and clearance in Alzheimer’s disease (AD) pathogenesis have been relatively little studied. Short Aβ-fragments form by enzymatic cleavage and alternate amyloid-beta precursor protein (APP)-processing. Here we characterized a novel polyclonal Aβ-antibody raised against an Aβ mid-domain and used it to investigate microglial Aβ-uptake in situ by microscopy at the light- and ultrastructural levels. The rabbit Aβ-mid-domain antibody (ab338), raised against the mid-domain amino acids 21–34 (Aβ21–34), was characterized with biochemical and histological techniques. To identify the epitope in Aβ recognized by ab338, solid phase and solution binding data were compared with peptide folding scores as calculated with the Tango software. The ab338 antibody displayed high average affinity (KD: 6.2 × 10−10 M) and showed preference for C-terminal truncated Aβ-peptides ending at amino acid 34 and Aβ-mid domain peptides with high scores of β-turn structure. In transgenic APP-mouse brain, ab338 labelled amyloid plaques and detected Aβ-fragments in microglia at the ultra- and light microscopic levels. This reinforces a role of microglia/macrophages in Aβ-clearance in vivo. The ab338 antibody might be a valuable tool to study Aβ-clearance by microglial uptake and Aβ-mid-domain peptides generated by enzymatic degradation and alternate production.

• Knapskog, Anne Brita; Henjum, Kristi; Idland, Ane-Victoria; Eldholm, Rannveig Sakshaug; Persson, Karin Ester Torun & Saltvedt, Ingvild [Show all 9 contributors for this article] (2020). Cerebrospinal fluid sTREM2 in Alzheimer’s disease: comparisons between clinical presentation and AT classification. Scientific Reports. 10, p. 1–10. doi: 10.1038/s41598-020-72878-8. Full text in Research Archive Show summary

  Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed by microglia. Its cleaved fragments, soluble TREM2 (sTREM2), can be measured in the cerebrospinal fluid (CSF). Previous studies indicate higher CSF sTREM2 in symptomatic AD; however most of these studies have included biomarker positive AD cases and biomarker negative controls. The aim of the study was to explore potential differences in the CSF level of sTREM2 and factors associated with an increased sTREM2 level in patients diagnosed with mild cognitive impairment (MCI) or dementia due to AD compared with cognitively unimpaired controls as judged by clinical symptoms and biomarker category (AT). We included 299 memory clinic patients, 62 (20.7%) with AD-MCI and 237 (79.3%) with AD dementia, and 113 cognitively unimpaired controls. CSF measures of the core biomarkers were applied to determine AT status. CSF sTREM2 was analyzed by ELISA. Patients presented with comparable CSF sTREM2 levels as the cognitively unimpaired (9.6 ng/ml [SD 4.7] versus 8.8 ng/ml [SD 3.6], p = 0.27). We found that CSF sTREM2 associated with age-related neuroinflammation and tauopathy irrespectively of amyloid β, APOE ε4 status or gender. The findings were similar in both symptomatic and non-symptomatic individuals.

• Halaas, Nathalie Bodd; Henjum, Kristi; Blennow, Kaj; Dakhil, Shams; Idland, Ane-Victoria & Nilsson, Lars [Show all 13 contributors for this article] (2019). CSF sTREM2 and Tau Work Together in Predicting Increased Temporal Lobe Atrophy in Older Adults. Cerebral Cortex. ISSN 1047-3211. 00, p. 1–12. doi: 10.1093/cercor/bhz240. Full text in Research Archive Show summary

  Neuroinflammation may be a key factor in brain atrophy in aging and age-related neurodegenerative disease. The objective of this study was to test the association between microglial expression of soluble Triggering Receptor Expressed on Myeloid Cells 2 (sTREM2), as a measure of neuroinflammation, and brain atrophy in cognitively unimpaired older adults. Brain magnetic resonance imagings (MRIs) and cerebrospinal fluid (CSF) sTREM2, total tau (t-tau), phosphorylated181 tau (p-tau), and Aβ42 were analyzed in 115 cognitively unimpaired older adults, classified according to the A/T/(N)-framework. MRIs were repeated after 2 (n = 95) and 4 (n = 62) years. High baseline sTREM2 was associated with accelerated cortical thinning in the temporal cortex of the left hemisphere, as well as bilateral hippocampal atrophy, independently of age, Aβ42, and tau. sTREM2-related atrophy only marginally increased with biomarker positivity across the AD continuum (A−T− #x2292; A+T− #x2292; A+T+) but was significantly stronger in participants with a high level of p-tau (T+). sTREM2-related cortical thinning correlated significantly with areas of high microglial-specific gene expression in the Allen Human Brain Atlas. In conclusion, increased CSF sTREM2 was associated with accelerated cortical and hippocampal atrophy in cognitively unimpaired older participants, particularly in individuals with tau pathology. This suggests a link between neuroinflammation, neurodegeneration, and amyloid-independent tauopathy.

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