Publications by authors named "Christina Unger Lithner"

11 Publications

  • Page 1 of 1

Homomeric and Heteromeric Aβ Species Exist in Human Brain and CSF Regardless of Alzheimer's Disease Status and Risk Genotype.

Front Mol Neurosci 2019 31;12:176. Epub 2019 Jul 31.

Department of Neurobiology, Care Sciences and Society, Division of Clinical Geriatrics, Center for Alzheimer Research, Karolinska Institutet (KI), Stockholm, Sweden.

: A fundamental question in Alzheimer's disease (AD) is whether amyloid-β (Aβ) peptides and their deposition in the brain signify a direct pathological role or they are mere outcome of the disease pathophysiological events affecting neuronal function. It is therefore important to decipher their physiological role in the brain. So far, the overwhelming focus has been on the potential toxicity of Aβ, often studied outside the crucial AD characteristics, i.e.: (i) the slow, decades-long disease progression that precedes clinical symptoms; (ii) the link to apolipoprotein-E ε4 allele as major risk factor; (iii) the selective early degeneration of cholinergic neurons. Previous studies, and cerebrospinal fluid (CSF) only, indicated one possible native function of Aβ peptides is the allosteric modulation of acetylcholine homeostasis, molecular interactions between Aβ, apolipoprotein-E, and the acetylcholine-degrading enzymes, cholinesterases, resulting in the formation of acetylcholine-hydrolyzing complexes (BAβACs). : Here, by combining sucrose-density gradient fractionation of post-mortem brains and in-house developed sensitive ELISA assays on the obtained fractions, we investigated the presence, levels and molecular interactions between Aβ, apolipoprotein-E and cholinesterases for the first time in brain tissues. We examined three distinct brain regions of Alzheimer and non-demented subjects, plus a large number of Alzheimer CSF samples. : We report that both monomeric and oligomeric (homomeric and heteromeric) forms of Aβ peptides are present in the brain of Alzheimer and non-demented individuals. Heteromeric Aβ was found in stable complexes with apolipoprotein-E and/or cholinesterases, irrespective of genotype or disease status, arguing in favor of a physiological dynamic formation and function for these complexes in the brain. The patterns and molecular sizes of the detected soluble Aβ forms were closely matched between CSF and brain samples. This evinces that the detected Aβ-apolipoprotein-E complexes and BAβACs in CSF most likely originate from the interstitial fluids of the brain. : In conclusion, both light homomeric Aβ oligomers and heteromeric Aβ-ApoE and BAβACs are present and readily detectable in the brain, regardless of disease status and genotype. Deeper knowledge of the physiological function of Aβ is crucial for better understanding the early pathological events that decades later lead to manifestation of AD.
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http://dx.doi.org/10.3389/fnmol.2019.00176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684963PMC
July 2019

Increased Active OMI/HTRA2 Serine Protease Displays a Positive Correlation with Cholinergic Alterations in the Alzheimer's Disease Brain.

Mol Neurobiol 2019 Jul 25;56(7):4601-4619. Epub 2018 Oct 25.

Division of Neurogeriatrics, Center for Alzheimer Research, NVS Department, Karolinska Institutet, 141 83, Huddinge, Sweden.

OMI/HTRA2 (high-temperature requirement serine protease A2) is a mitochondrial serine protease involved in several cellular processes, including autophagy, chaperone activity, and apoptosis. Few studies on the role of OMI/HTRA2 in Alzheimer's disease (AD) are available, but none on its relationship with the cholinergic system and neurotrophic factors as well as other AD-related proteins. In this study, immunohistochemical analyses revealed that AD patients had a higher cytosolic distribution of OMI/HTRA2 protein compared to controls. Quantitative analyses on brain extracts indicated a significant increase in the active form of OMI/HTRA2 in the AD brain. Activated OMI/HTRA2 protein positively correlated with stress-associated read-through acetylcholinesterase activity. In addition, α7 nicotinic acetylcholine receptor gene expression, a receptor also known to be localized on the outer membrane of mitochondria, showed a strong correlation with OMI/HTRA2 gene expression in three different brain regions. Interestingly, the activated OMI/HTRA2 levels also correlated with the activity of the acetylcholine-biosynthesizing enzyme, choline acetyltransferase (ChAT); with levels of the neurotrophic factors, NGF and BDNF; with levels of the soluble fragments of amyloid precursor protein (APP); and with gene expression of the microtubule-associated protein tau in the examined brain regions. Overall, the results demonstrate increased levels of the mitochondrial serine protease OMI/HTRA2, and a coherent pattern of association between the activated form of OMI/HTRA2 and several key proteins involved in AD pathology. In this paper, we propose a new hypothetical model to highlight the importance and needs of further investigation on the role of OMI/HTRA2 in the mitochondrial function and AD.
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http://dx.doi.org/10.1007/s12035-018-1383-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657433PMC
July 2019

Soluble Aβ42 Acts as Allosteric Activator of the Core Cholinergic Enzyme Choline Acetyltransferase.

Front Mol Neurosci 2018 13;11:327. Epub 2018 Sep 13.

Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.

Two major questions in the field of Alzheimer-type dementia remain elusive. One is the native function of amyloid-β (Aβ) peptides and the other is an early deficit in the central cholinergic network. Nevertheless, recent evidence suggests that Aβ peptides are involved in the regulation of acetylcholine (ACh) homeostasis either by allosteric activation of ACh-degrading cholinesterases or by inhibiting the high-affinity choline uptake transporter. In the current study, we report that Aβ peptides, in particular Aβ42, allosterically enhances the catalytic rate of the core-cholinergic enzyme choline acetyltransferase (ChAT), responsible for biosynthesis of ACh. Detailed enzyme kinetic analysis indicated that both soluble Aβ40 and Aβ42 enhanced the catalytic efficiency of ChAT by ∼21% and 26% at physiological concentration ranges found in human cerebrospinal fluid (CSF). Further analyses indicated that activation of ChAT by Aβ was highly specific. Intriguingly, Aβ42 exhibited an EC of activation potency at 10-fold lower concentrations compared to Aβ40. The activation was persistent even in the presence of a physiological Aβ 40/42 mixture ratio, expected in human CSF. In conclusion, we report for the first time that Aβ42 peptide acts as allosteric enhancers of ACh-biosynthesizing enzyme ChAT. Together with two previous observations, this points to a complex molecular cross-talk between Aβ and the enzymatic machinery involved in maintaining cellular, synaptic and extra-synaptic ACh homeostasis, warranting further investigation.
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http://dx.doi.org/10.3389/fnmol.2018.00327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6146036PMC
September 2018

Perforin Promotes Amyloid Beta Internalisation in Neurons.

Mol Neurobiol 2017 03 16;54(2):874-887. Epub 2016 Jan 16.

Division for Neurogeriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Center for Alzheimer Research, Karolinska Institutet, Novum 5th floor, Huddinge, 141 57, Sweden.

Studies on the mechanisms of neuronal amyloid-β (Aβ) internalisation are crucial for understanding the neuropathological progression of Alzheimer's disease (AD). We here investigated how extracellular Aβ peptides are internalised and focused on three different pathways: (i) via endocytic mechanisms, (ii) via the receptor for advanced glycation end products (RAGE) and (iii) via the pore-forming protein perforin. Both Aβ and Aβ were internalised in retinoic acid differentiated neuroblastoma (RA-SH-SY5Y) cells. A higher concentration was required for Aβ (250 nM) compared with Aβ (100 nM). The internalised Aβ showed a dot-like pattern of distribution whereas Aβ accumulated in larger and distinct formations. By confocal microscopy, we showed that Aβ and Aβ co-localised with mitochondria, endoplasmic reticulum (ER) and lysosomes. Aβ treatment of human primary cortical neurons (hPCN) confirmed our findings in RA-SH-SY5Y cells, but hPCN were less sensitive to Aβ; therefore, a 20 (Aβ) and 50 (Aβ) times higher concentration was needed for inducing uptake. The blocking of endocytosis completely inhibited the internalisation of Aβ peptides in RA-SH-SY5Y cells and hPCN, indicating that this is a major pathway by which Aβ enters the cells. In addition, the internalisation of Aβ, but not Aβ, was reduced by 55 % by blocking RAGE. Finally, for the first time we showed that pore formation in cell membranes by perforin led to Aβ internalisation in hPCN. Understanding how Aβ is internalised sheds light on the pathological role of Aβ and provides further ideas of inhibitory strategies for preventing Aβ internalisation and the spreading of neurodegeneration in AD.
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http://dx.doi.org/10.1007/s12035-016-9685-9DOI Listing
March 2017

Pregnancy outcome for fetuses with increased nuchal translucency but normal karyotype.

J Med Screen 2016 Mar 20;23(1):1-6. Epub 2015 Jul 20.

Karolinska University Hospital, Department of Obstetrics and Gynecology, Center of Fetal Medicine, 14186 Stockholm, Sweden

Objective: To investigate pregnancy outcome for fetuses with nuchal translucency (NT) ≥3.5 mm but normal karyotype in the Stockholm (Sweden) area.

Methods: A retrospective population-based cohort study. From 2006 to 2012, fetal NT was measured in 55123 singleton pregnancies. There were 341 pregnancies with NT thickness ≥3.5 mm; 139 had a normal karyotype, 164 had an abnormal karyotype and 38 were removed from the study. Pregnancy outcome was defined as adverse (termination of pregnancy [TOP], miscarriage [MC], intrauterine fetal death [IUFD], or delivery of a child with structural defects or genetic disorders), or favourable (delivery of a child without any structural defects or genetic disorders diagnosed before discharge).

Results: Of the 139 high NT pregnancies with normal karyotype, 110 (79.2%) resulted in live births, one (0.7%) IUFD, 23 (16.5%) TOP and five (3.6%) MC. The risk of an adverse pregnancy outcome increased with increasing NT. Structural fetal defects were found in 28 (19.5%) of pregnancies undergoing second trimester ultrasound screening, of which seven resulted in live births and 21 were terminated. The most common structural defect was cardiac defects.

Conclusions: Adverse pregnancy outcome increased with increasing NT, even with normal karyotype, however, the prognosis is good if the second trimester ultrasound screening is normal.
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http://dx.doi.org/10.1177/0969141315595826DOI Listing
March 2016

High apolipoprotein E in cerebrospinal fluid of patients with Lewy body disorders is associated with dementia.

Alzheimers Dement 2014 Sep 24;10(5):530-540.e1. Epub 2013 Aug 24.

Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Alzheimer Neurobiology Center, Stockholm, Sweden. Electronic address:

Apolipoprotein E ε4 allele (APOE ε4) increases the apolipoprotein E (apoE) protein levels in Alzheimer's disease (AD) cerebrospinal fluid (CSF). Thus, we hypothesized that apoE levels were also associated with the APOE genotype, and amyloid-β (Aβ)-associated clinical, functional, and imaging parameters in patients with Lewy body-associated disorders (LBD). Indeed, similar to AD, patients with LBD displayed high CSF apoE levels (greatest in patients with dementia with LBD), and this was linked to APOE ε4. High CSF apoE protein correlated positively with CSF soluble amyloid precursor protein, total tau, and cortical and striatal Pittsburgh compound B retention; and correlated negatively with CSF Aβ42, cognitive tests scores, and glucose uptake ratio in the temporal and parietal cortices. APOE ε4-triggered accumulation of apoE in CSF is related to Aβ-associated clinical and functional imaging parameters in LBD. Accordingly, therapeutic strategies aimed at reducing apoE levels in the brain should be explored not only in AD but also in LBD, particularly when accompanied with dementia.
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http://dx.doi.org/10.1016/j.jalz.2013.03.010DOI Listing
September 2014

Disruption of neocortical histone H3 homeostasis by soluble Aβ: implications for Alzheimer's disease.

Neurobiol Aging 2013 Sep 9;34(9):2081-90. Epub 2013 Apr 9.

Alzheimer Neurobiology Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.

Amyloid-β peptide (Aβ) fragment misfolding may play a crucial role in the progression of Alzheimer's disease (AD) pathophysiology as well as epigenetic mechanisms at the DNA and histone level. We hypothesized that histone H3 homeostasis is disrupted in association with the appearance of soluble Aβ at an early stage in AD progression. We identified, localized, and compared histone H3 modifications in multiple model systems (neural-like SH-SY5Y, primary neurons, Tg2576 mice, and AD neocortex), and narrowed our focus to investigate 3 key motifs associated with regulating transcriptional activation and inhibition: acetylated lysine 14, phosphorylated serine 10 and dimethylated lysine 9. Our results in vitro and in vivo indicate that multimeric soluble Aβ may be a potent signaling molecule indirectly modulating the transcriptional activity of DNA by modulating histone H3 homeostasis. These findings reveal potential loci of transcriptional disruption relevant to AD. Identifying genes that undergo significant epigenetic alterations in response to Aβ could aid in the understanding of the pathogenesis of AD, as well as suggesting possible new treatment strategies.
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http://dx.doi.org/10.1016/j.neurobiolaging.2012.12.028DOI Listing
September 2013

Age-dependent neuroplasticity mechanisms in Alzheimer Tg2576 mice following modulation of brain amyloid-β levels.

PLoS One 2013 15;8(3):e58752. Epub 2013 Mar 15.

Alzheimer Neurobiology Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.

The objective of this study was to investigate the effects of modulating brain amyloid-β (Aβ) levels at different stages of amyloid pathology on synaptic function, inflammatory cell changes and hippocampal neurogenesis, i.e. processes perturbed in Alzheimer's disease (AD). Young (4- to 6-month-old) and older (15- to 18-month-old) APP(SWE) transgenic (Tg2576) mice were treated with the AD candidate drug (+)-phenserine for 16 consecutive days. We found significant reductions in insoluble Aβ1-42 levels in the cortices of both young and older transgenic mice, while significant reductions in soluble Aβ1-42 levels and insoluble Aβ1-40 levels were only found in animals aged 15-18 months. Autoradiography binding with the amyloid ligand Pittsburgh Compound B ((3)H-PIB) revealed a trend for reduced fibrillar Aβ deposition in the brains of older phenserine-treated Tg2576 mice. Phenserine treatment increased cortical synaptophysin levels in younger mice, while decreased interleukin-1β and increased monocyte chemoattractant protein-1 and tumor necrosis factor-alpha levels were detected in the cortices of older mice. The reduction in Aβ1-42 levels was associated with an increased number of bromodeoxyuridine-positive proliferating cells in the hippocampi of both young and older Tg2576 mice. To determine whether the increased cell proliferation was accompanied by increased neuronal production, the endogenous early neuronal marker doublecortin (DCX) was examined in the dentate gyrus (DG) using immunohistochemical detection. Although no changes in the total number of DCX(+)-expressing neurons were detected in the DG in Tg2576 mice at either age following (+)-phenserine treatment, dendritic arborization was increased in differentiating neurons in young Tg2576 mice. Collectively, these findings indicate that reducing Aβ1-42 levels in Tg2576 mice at an early pathological stage affects synaptic function by modulating the maturation and plasticity of newborn neurons in the brain. In contrast, lowering Aβ levels in Tg2576 mice when Aβ plaque pathology is prominent mainly alters the levels of proinflammatory cytokines and chemokines.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0058752PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598857PMC
October 2013

Transgenic mice as a model for Alzheimer's disease.

Curr Alzheimer Res 2011 Dec;8(8):818-31

Karolinska Institutet, NVS, Division of Alzheimer Neurobiology, Novum Floor 4, Karolinska University Hospital, Huddinge, S-141 86 Stockholm, Sweden.

During the last few decades, numerous stable transgenic mouse strains have been developed in order to mimic a range of Alzheimer's disease (AD)-related pathologies. Although none of the models fully replicates the human disease, the models have been a key feature in translational research, providing significant insights into the pathophysiology of AD. They have also been widely used in the preclinical testing of potential therapies. The choice of transgenic mouse model, as well as the stage of Aβ pathology, significantly contributes to the outcome of the studies. Therefore, it is important to combine studies in different transgenic mouse models and detailed in vitro experiments to obtain a complete understanding of the origin of the disease, the actual sequences of early pathological events as well as being able to evaluate the effects of new drugs in the treatment of AD.
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http://dx.doi.org/10.2174/156720511798192736DOI Listing
December 2011

Characterization of the brain β-amyloid isoform pattern at different ages of Tg2576 mice.

Neurodegener Dis 2011 23;8(5):352-63. Epub 2011 Feb 23.

Division of Alzheimer Neurobiology, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.

Background: Although genetic and biochemical studies have suggested a cardinal role for β-amyloid (Aβ) in Alzheimer's disease, the underlying mechanism(s) of how Aβ induces neurodegeneration is still unclear. Our objective was to investigate the consequences of Aβ, especially on tau phosphorylation at specific epitopes important for Alzheimer's disease.

Methods: We used cortices from Tg2576 mice at 7 days to 15 months of age.

Results: MALDI-TOF MS revealed an age-dependent shift in the Aβ isoform pattern. Young animals displayed high cortical levels of the shorter Aβ isoforms (Aβ1-16 and Aβ1-17) compared to 15-month-old Tg2576 mice which mainly expressed Aβ1-40 and Aβ1-42. The Aβ1-42 showed an age-dependent increase, whereas total Aβ1-40 levels remained constant. The highest levels of TBS-soluble Aβ oligomers were found at 90 days of age. Brain Aβ build-up did not affect the phosphorylation of tau at the epitopes investigated.

Conclusions: This study provides new information about age-dependent Aβ isoforms and oligomers as well as their effect on site-specific tau phosphorylation in this transgenic mouse model. Our observations suggest that the different human Aβ isoforms do not directly cause increased tau phosphorylation and that the cognitive deficits seen in this mouse model are only related to the Aβ overexpression.
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http://dx.doi.org/10.1159/000323871DOI Listing
May 2012

Effect of huprine X on β-amyloid, synaptophysin and α7 neuronal nicotinic acetylcholine receptors in the brain of 3xTg-AD and APPswe transgenic mice.

Neurodegener Dis 2010 4;7(6):379-88. Epub 2010 Aug 4.

Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Division of Alzheimer Neurobiology, Karolinska University Hospital, Huddinge, Stockholm, Sweden.

Background: Several studies implicate acetylcholinesterase (AChE) in the pathogenesis of Alzheimer's disease (AD), raising the question of whether inhibitors of AChE also might act in a disease-modifying manner. Huprine X (HX), a reversible AChE inhibitor hybrid of tacrine and huperzine A, has shown to affect the amyloidogenic process in vitro. In this study, the aim was to investigate whether HX could affect the AD-related neuropathology in vivo in two mouse models.

Methods: Tg2576 (K670M/N671L) (APPswe) and 3xTg-AD (K670M/N671L, PS1M146V, tauP301L) mice were treated with HX (0.12 μmol/kg, i.p., 21 days) or saline at 6-7 months. Human β-amyloid (Aβ) was measured by ELISA, synaptophysin by Western blot and α7 neuronal nicotinic acetylcholine receptors (nAChRs) were analyzed by [(125)I]α-bungarotoxin autoradiography.

Results: Treatment with HX reduced insoluble Aβ1-40 (about 40%) in the hippocampus of 3xTg-AD mice, while showing no effect in APPswe mice. Additionally, HX markedly increased cortical synaptophysin levels (about 140%) and decreased (about 30%) the levels of α7 nAChRs in the caudate nucleus of 3xTg-AD mice, while increasing (about 10%) hippocampal α7 nAChRs in APPswe mice.

Conclusion: The two mouse models react differently to HX treatment, possibly due to their differences in brain neuropathology. The modulation of Aβ and synaptophysin by HX in 3xTg-AD mice might be due to its suggested interaction with the peripheral anionic site on AChE, and/or via cholinergic mechanisms involving activation of cholinergic receptors. Our results provide further evidence that drugs targeting AChE affect some of the fundamental processes that contribute to neurodegeneration, but whether HX might act in a disease-modifying manner in AD patients remains to be proven.
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http://dx.doi.org/10.1159/000287954DOI Listing
February 2011