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Hellström, Lotta
Alternative names
Publications (10 of 11) Show all publications
Agholme, L. & Hallbeck, M. (2014). Getting rid of intracellular Aβ- loss of cellular degradation leads to transfer between connected neurons. Current pharmaceutical design, 20(15), 2458-2468
Open this publication in new window or tab >>Getting rid of intracellular Aβ- loss of cellular degradation leads to transfer between connected neurons
2014 (English)In: Current pharmaceutical design, ISSN 1381-6128, E-ISSN 1873-4286, Vol. 20, no 15, p. 2458-2468Article in journal (Refereed) Published
Abstract [en]

The sporadic, late onset form of Alzheimers disease (AD) shares pathological hallmarks with the familial form; however, no clear reason for increased beta-amyloid (A beta) generation has been found in the former. It has long been speculated that the late onset form of AD is caused by reduced degradation and/or clearance of A beta. Indeed, both intracellular degradation systems, the proteasomal and lysosomal systems, have been shown to be defective in AD. Reduced proteasome activity increases levels of intracellular and secreted A beta. Furthermore, accumulation of improperly degraded A beta in the lysosomes causes lysosomal disruption and cell death. We recently showed that oligomeric A beta can be transmitted from one neuron to another, which causes neurotoxicity. In both the donating and receiving cells, A beta accumulates in the endo-lysosomal compartment. It is possible that ineffective degradation of A beta causes its transfer to neighboring neurons, thereby spreading AD pathology. This review summarizes the data underlying the idea of reduced A beta clearance and subsequent A beta spread in AD, and also suggests new therapeutic methods, which are aimed at targeting the degradation systems and synaptic transfer. By enhancing degradation of intracellular accumulated A beta, it can be possible to remove it and avoid A beta-induced neurodegeneration without disturbing the endogenously important pool of secreted A beta. Additionally, drugs targeted to inhibit the spread of intracellular toxic A beta aggregates may also be useful in stopping the progression of pathology, without affecting the level of A beta that normally occurs in the brain.

Place, publisher, year, edition, pages
Bentham Science Publishers, 2014
Keywords
Alzheimers disease; lysosome; proteasome; beta-amyloid; neuron-to-neuron transfer; degradation
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-107844 (URN)10.2174/13816128113199990501 (DOI)000336169300002 ()23859554 (PubMedID)
Available from: 2014-06-23 Created: 2014-06-23 Last updated: 2019-10-14Bibliographically approved
Armstrong, A., Mattsson, N., Appelqvist, H., Janefjord, C., Sandin, L., Agholme, L., . . . Kågedal, K. (2014). Lysosomal Network Proteins as Potential Novel CSF Biomarkers for Alzheimers Disease. Neuromolecular medicine, 16(1), 150-160
Open this publication in new window or tab >>Lysosomal Network Proteins as Potential Novel CSF Biomarkers for Alzheimers Disease
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2014 (English)In: Neuromolecular medicine, ISSN 1535-1084, E-ISSN 1559-1174, Vol. 16, no 1, p. 150-160Article in journal (Refereed) Published
Abstract [en]

The success of future intervention strategies for Alzheimers disease (AD) will likely rely on the development of treatments starting early in the disease course, before irreversible brain damage occurs. The pre-symptomatic stage of AD occurs at least one decade before the clinical onset, highlighting the need for validated biomarkers that reflect this early period. Reliable biomarkers for AD are also needed in research and clinics for diagnosis, patient stratification, clinical trials, monitoring of disease progression and the development of new treatments. Changes in the lysosomal network, i.e., the endosomal, lysosomal and autophagy systems, are among the first alterations observed in an AD brain. In this study, we performed a targeted search for lysosomal network proteins in human cerebrospinal fluid (CSF). Thirty-four proteins were investigated, and six of them, early endosomal antigen 1 (EEA1), lysosomal-associated membrane proteins 1 and 2 (LAMP-1, LAMP-2), microtubule-associated protein 1 light chain 3 (LC3), Rab3 and Rab7, were significantly increased in the CSF from AD patients compared with neurological controls. These results were confirmed in a validation cohort of CSF samples, and patients with no neurochemical evidence of AD, apart from increased total-tau, were found to have EEA1 levels corresponding to the increased total-tau levels. These findings indicate that increased levels of LAMP-1, LAMP-2, LC3, Rab3 and Rab7 in the CSF might be specific for AD, and increased EEA1 levels may be a sign of general neurodegeneration. These six lysosomal network proteins are potential AD biomarkers and may be used to investigate lysosomal involvement in AD pathogenesis.

Place, publisher, year, edition, pages
Humana Press, 2014
Keywords
PICALM; DRAM; TFEB; Cathepsins; Proteasome; hsc70
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-105235 (URN)10.1007/s12017-013-8269-3 (DOI)000331101900015 ()
Available from: 2014-03-14 Created: 2014-03-14 Last updated: 2018-01-11
Agholme, L., Nath, S., Domert, J., Marcusson, J., Kågedal, K. & Hallbeck, M. (2014). Proteasome Inhibition Induces Stress Kinase Dependent Transport Deficits – Implications for Alzheimer’s Disease. Molecular and Cellular Neuroscience, 58, 29-39
Open this publication in new window or tab >>Proteasome Inhibition Induces Stress Kinase Dependent Transport Deficits – Implications for Alzheimer’s Disease
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2014 (English)In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 58, p. 29-39Article in journal (Refereed) Published
Abstract [en]

Alzheimer’s disease (AD) is characterized by accumulation of two misfolded and aggregated proteins, β-amyloid and hyperphosphorylated tau. Both cellular systems responsible for clearance of misfolded and aggregated proteins, the lysosomal and the proteasomal, have been shown to be malfunctioning in the aged brain and more so in AD patients. This malfunction could be the cause of β-amyloid and tau accumulation, eventually aggregating in plaques and tangles. We have investigated how decreased proteasome activity affects AD related pathophysiological changes of microtubule transport and stability, as well as tau phosphorylation. To do this, we used our recently developed neuronal model where human SH-SY5Y cells obtain neuronal morphology and function through differentiation. We found that exposure to low doses of the proteasome inhibitor MG-115 caused disturbed neuritic transport, together with microtubule destabilization and tau phosphorylation. Furthermore, reduced proteasome activity activated several kinases implicated in AD pathology, including JNK, c-Jun and ERK 1/2. Restoration of the microtubule transport was achieved by inhibiting ERK 1/2 activation, and simultaneous inhibition of both ERK 1/2 and c-Jun reversed the proteasome inhibition-induced tau phosphorylation. Taken together, this study suggests that a decrease in proteasome activity can, through activation of c-Jun and ERK 1/2, result in several events contributing to AD pathology. Restoring proteasome function or inhibiting ERK 1/2 and c-Jun could therefore be used as novel treatments against AD.

Place, publisher, year, edition, pages
Elsevier, 2014
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-81339 (URN)10.1016/j.mcn.2013.11.001 (DOI)000331853600004 ()
Available from: 2012-09-12 Created: 2012-09-12 Last updated: 2019-10-14Bibliographically approved
Domert, J., Rao, S. B., Agholme, L., Brorsson, A.-C., Marcusson, J., Hallbeck, M. & Nath, S. (2014). Spreading of Amyloid-β Peptides via Neuritic Cell-to-cell Transfer Is Dependent on Insufficient Cellular Clearance. Neurobiology of Disease, 65, 82-92
Open this publication in new window or tab >>Spreading of Amyloid-β Peptides via Neuritic Cell-to-cell Transfer Is Dependent on Insufficient Cellular Clearance
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2014 (English)In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 65, p. 82-92Article in journal (Refereed) Published
Abstract [en]

The spreading of pathology through neuronal pathways is likely to be the cause of the progressive cognitive loss observed in Alzheimer's disease (AD) and other neurodegenerative diseases. We have recently shown the propagation of AD pathology via cell-to-cell transfer of oligomeric amyloid beta (Aβ) residues 1-42 (oAβ1-42) using our donor-acceptor 3-D co-culture model. We now show that different Aβ-isoforms (fluorescently labeled 1-42, 3(pE)-40, 1-40 and 11-42 oligomers) can transfer from one cell to another. Thus, transfer is not restricted to a specific Aβ-isoform. Although different Aβ isoforms can transfer, differences in the capacity to clear and/or degrade these aggregated isoforms result in vast differences in the net amounts ending up in the receiving cells and the net remaining Aβ can cause seeding and pathology in the receiving cells. This insufficient clearance and/or degradation by cells creates sizable intracellular accumulations of the aggregation-prone Aβ1-42 isoform, which further promotes cell-to-cell transfer; thus, oAβ1-42 is a potentially toxic isoform. Furthermore, cell-to-cell transfer is shown to be an early event that is seemingly independent of later appearances of cellular toxicity. This phenomenon could explain how seeds for the AD pathology could pass on to new brain areas and gradually induce AD pathology, even before the first cell starts to deteriorate, and how cell-to-cell transfer can act together with the factors that influence cellular clearance and/or degradation in the development of AD.

Place, publisher, year, edition, pages
Elsevier, 2014
Keywords
Alzheimer's disease, Amyloid-β oligomers, Cell-to-cell transfer, Intracellular accumulation, Prion-like propagation
National Category
Cell Biology
Identifiers
urn:nbn:se:liu:diva-103179 (URN)10.1016/j.nbd.2013.12.019 (DOI)000333546300008 ()24412310 (PubMedID)
Available from: 2014-01-14 Created: 2014-01-14 Last updated: 2019-10-14Bibliographically approved
Agholme, L., Hallbeck, M., Benedikz, E., Marcusson, J. & Kågedal, K. (2012). Amyloid-β Secretion, Generation, and Lysosomal Sequestration in Response to Proteasome Inhibition: Involvement of Autophagy. Journal of Alzheimer's Disease, 31(2), 343-358
Open this publication in new window or tab >>Amyloid-β Secretion, Generation, and Lysosomal Sequestration in Response to Proteasome Inhibition: Involvement of Autophagy
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2012 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 31, no 2, p. 343-358Article in journal (Refereed) Published
Abstract [en]

The proteasome is important for degradation of worn out and misfolded proteins. Decreased proteasome activity has been implicated in Alzheimer's disease (AD). Proteasome inhibition induces autophagy, but it is still unknown whether autophagy is beneficial or deleterious to AD neurons, as the autophagosome has been suggested as a site of amyloid-β (Aβ) generation. In this study, we investigated the effect of proteasome inhibition on Aβ accumulation and secretion, as well as the processing of amyloid-β protein precursor (AβPP) in AβPPSwe transfected SH-SY5Y neuroblastoma cells. We show that proteasome inhibition resulted in autophagy-dependent accumulation of Aβ in lysosomes, and increased levels of intracellular and secreted Aβ. The enhanced levels of Aβ could not be explained by increased amounts of AβPP. Instead, reduced degradation of the C-terminal fragment of AβPP (C99) by the proteasome makes C99 available for γ-secretase cleavage, leading to Aβ generation. Inhibition of autophagy after proteasome inhibition led to reduced levels of intracellular, but not secreted Aβ, and tended to further increase the C99 to AβPP ratio, supporting involvement of the autophagosome in Aβ generation. Furthermore, proteasome inhibition caused a reduction in cellular viability, which was reverted by inhibition of autophagy. Dysfunction of the proteasome could cause lysosomal accumulation of Aβ, as well as increased generation and secretion of Aβ, which is partly facilitated by autophagy. As a decrease in cellular viability was also detected, it is possible that upregulation of autophagy is an unsuccessful rescue mechanism, which instead of being protective, contributes to AD pathogenesis.

Place, publisher, year, edition, pages
I O S Press, 2012
Keywords
AβPP processing, Alzheimer’s disease, amyloid- peptide, autophagy, cell death, LC-3, lysosome, p70S6K, proteasome
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81340 (URN)10.3233/JAD-2012-120001 (DOI)000307377300011 ()22555375 (PubMedID)
Note

funding agencies|foundations of Engqvist, Wiberg, Hedlund, Osterman, and Stohne||Gustav V and Queen Victorias Foundation||Swedish Alzheimers foundation||Ostergotland County Council||Swedish Research Council||

Available from: 2012-09-12 Created: 2012-09-12 Last updated: 2019-10-14Bibliographically approved
Klionsky, D. J., Abdalla, F. C., Abeliovich, H., Abraham, R. T., Acevedo-Arozena, A., Adeli, K., . . . Zuckerbraun, B. (2012). Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy, 8(4), 445-544
Open this publication in new window or tab >>Guidelines for the use and interpretation of assays for monitoring autophagy
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2012 (English)In: Autophagy, ISSN 1554-8627, Vol. 8, no 4, p. 445-544Article, review/survey (Refereed) Published
Abstract [en]

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

Place, publisher, year, edition, pages
Landes Bioscience, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-82027 (URN)10.4161/auto.19496 (DOI)000305403400002 ()22966490 (PubMedID)
Available from: 2012-09-28 Created: 2012-09-28 Last updated: 2017-01-16
Agholme, L. (2012). The involvement of degradation pathways and neuron-to-neuron transmission in Alzheimer’s disease. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>The involvement of degradation pathways and neuron-to-neuron transmission in Alzheimer’s disease
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Although the vast majority of Alzheimer’s disease (AD) cases are of the sporadic type, mutations causing the familial form have been the focus of AD research for decades. The disease is pathologically characterised by β-amyloid (Aβ) and tau protein aggregates in neuritic plaques and neurofibrillary tangles. Furthermore, it is known that AD pathology spreads throughout the brain, most often along the same anatomical pattern. However, so far no cause for the sporadic form of the disease has been found. Accumulation of protein aggregates as well as decreased activity of the protein degradation systems, lysosomes and proteasomes, is found in diseased brains. This indicates that defective degradation contributes to sporadic AD.

The aim of this thesis was to develop an improved neuronal model, and study the effects of decreased proteasome function on tau phosphorylation and axonal transport. In addition, the effects on Aβ accumulation and generation upon proteasome inhibition were investigated. Finally, the possibility that intracellularly accumulated Aβ oligomers could be transferred from one neuron to another was tested.

Differentiation of human SH-SY5Y neuroblastoma cells in an extracellular matrix gel, using a set of neurotrophic factors, resulted in cells with neuronal phenotype, expressing neuron specific markers and all six adult isoforms of tau. Within this neuronal model, we found that reduced proteasome activity inhibited neuritic transport, and caused tau phosphorylation in a c-Jun and ERK 1/2 dependent manner. Using proteasome inhibition in APP overexpressing cells, we found an autophagy dependent intralysosomal Aβ accumulation, together with elevation of intra- and extracellular concentrations of Aβ. Autophagy inhibition protected the cells from the toxicity induced by decreased proteasome activity. Finally, we could, as the first group, show that Aβ can be directly transferred from one neuron to another through connected neurites. Furthermore, accumulation of Aβ in the endo-lysosomal compartment of receiving cells caused toxicity and neurodegeneration.

We believe that cells not able to degrade accumulated Aβ, due to increased generation or reduced degradative capacity, instead tries to clear its content through transfer to connected neurons. If not properly degraded in the receiving cell, this can accelerate AD pathology and cause neuritic and neuronal degeneration spreading throughout the brain. Increasing the activity of the degradative systems, or inhibiting transmission of Aβ between neurons could therefore be novel treatments for AD.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. p. 69
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1317
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81341 (URN)978-91-7519-848-4 (ISBN)
Public defence
2012-10-05, Nils-Holger salen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2012-09-12 Created: 2012-09-12 Last updated: 2019-12-10Bibliographically approved
Agholme, L., Lindström, T., Kågedal, K., Marcusson, J. & Hallbeck, M. (2010). An In Vitro Model for Neuroscience: Differentiation of SH-SY5Y Cells into Cells with Morphological and Biochemical Characteristics of Mature Neurons. Journal of Alzheimer's Disease, 20(4), 1069-1082
Open this publication in new window or tab >>An In Vitro Model for Neuroscience: Differentiation of SH-SY5Y Cells into Cells with Morphological and Biochemical Characteristics of Mature Neurons
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2010 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 20, no 4, p. 1069-1082Article in journal (Refereed) Published
Abstract [en]

Neuroscience, including research on Alzheimers disease, is hampered by the lack of suitable in vitro models to study the human nervous system. To counteract this, many attempts to differentiate cell lines into more neuron-like cells have been performed, resulting in partial expression of neuronal features. Furthermore, it has been reported that neuroblastoma cell lines lack mature isoforms of tau. Our aim was to develop an improved in vitro model, generating sustainable cells with morphology and biochemistry of human, mature neurons. To obtain cells with neuronal differentiation and function, we investigated the effect of combining three-dimensional culturing of SH-SY5Y cells in extracellular matrix (ECM) gel with several factors reported to have neuro-differentiating effects. This resulted in cells with apparent neuronal morphology with long, extensively branched neurites. Further investigation revealed expression of several neurospecific markers including synapse protein Sv2 and nuclear marker NeuN, as well as the presence of synapses and axonal vesicle transport. In addition, these cells expressed mature tau isoforms, and tau protein expression was significantly increased compared to undifferentiated cells, reaching levels found in adult human brain. In conclusion, we found that pre-treatment with retinoic acid followed by ECM gel culturing in combination with brain derived neurotrophic factor, neuregulin beta(1), nerve growth factor, and vitamin D-3 treatment generated sustainable cells with unambiguous resemblance to adult neurons. These cells also expresses adult splicing forms of tau with neuronal localization, making this cellular in vitro model useful in many areas of neuroscience research, particularly the Alzheimers disease field.

Place, publisher, year, edition, pages
Ios Press, 2010
Keywords
Alzheimers disease; differentiation; in vitro model; neuroblastoma; tau
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-58227 (URN)10.3233/JAD-2010-091363 (DOI)000279539500012 ()
Note
Original Publication: Lotta Agholme, Tobias Lindström, Katarina Kågedal, Jan Marcusson and Martin Hallbeck, An In Vitro Model for Neuroscience: Differentiation of SH-SY5Y Cells into Cells with Morphological and Biochemical Characteristics of Mature Neurons, 2010, Journal of Alzheimer's Disease, (20), 4, 1069-1082. http://dx.doi.org/10.3233/JAD-2010-091363 Copyright: Ios Press http://www.iospress.nl/ Available from: 2010-08-10 Created: 2010-08-09 Last updated: 2019-10-14
Kim, W. S., Bhatia, S., Elliott, D. A., Agholme, L., Kågedal, K., McCann, H., . . . Garner, B. (2010). Increased ATP-binding cassette transporter A1 expression in Alzheimer's disease hippocampal neurons. Journal of Alzheimer's disease : JAD, 21(1), 193-205
Open this publication in new window or tab >>Increased ATP-binding cassette transporter A1 expression in Alzheimer's disease hippocampal neurons
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2010 (English)In: Journal of Alzheimer's disease : JAD, ISSN 1875-8908, Vol. 21, no 1, p. 193-205Article in journal (Refereed) Published
Abstract [en]

ATP-binding cassette transporter A1 (ABCA1) reduces amyloid-beta burden in transgenic mouse models of Alzheimer's disease (AD). Associations between ABCA1 polymorphisms and AD risk are also established. Little is known regarding the regulation of ABCA1 expression in the brain and how this may be affected by AD. In the present study we assessed ABCA1 mRNA and protein expression in the hippocampus of AD cases compared to controls. ABCA1 was clearly expressed in hippocampal neurons and expression was increased two- to three-fold in AD cases. The increased hippocampal ABCA1 expression was associated with increased APOE and PUMA gene expression, implying an association with neuronal stress. Consistent with this, treatment of SK-N-SH neurons with amyloid-beta peptide resulted in a 48% loss in survival and a significant upregulation of ABCA1, APOE, and PUMA gene expression. Studies in young (2 month) and old (12 month) transgenic mice expressing a familial AD form of human amyloid-beta protein precursor and presenilin-1 revealed a significant age-dependent upregulation of hippocampal Abca1 compared to wild-type control mice. However, hippocampal Apoe and Puma gene expression were not correlated with increased Abca1 expression in mice. Our data indicate that ABCA1 is upregulated in AD hippocampal neurons potentially via an amyloid-beta-mediated pathway.

Keywords
ABCA1, Alzheimer's disease, amyloid-β peptide, ATP-binding cassette transporter A1, hippocampus, neurodegeneration
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-59485 (URN)10.3233/JAD-2010-100324 (DOI)20413849 (PubMedID)
Available from: 2010-09-16 Created: 2010-09-16 Last updated: 2010-09-17
Kågedal, K., Scott Kim, W., Appelqvist, H., Chan, S., Cheng, D., Agholme, L., . . . Garner, B. (2010). Increased expression of the lysosomal cholesterol transporter NPC1 in Alzheimers disease. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, 1801(8), 831-838
Open this publication in new window or tab >>Increased expression of the lysosomal cholesterol transporter NPC1 in Alzheimers disease
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2010 (English)In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, ISSN 1388-1981, E-ISSN 1879-2618, Vol. 1801, no 8, p. 831-838Article in journal (Refereed) Published
Abstract [en]

The Niemann-Pick type Cl (NPC1) protein mediates the trafficking of cholesterol from lysosomes to other organelles. Mutations in the NPC1 gene lead to the retention of cholesterol and other lipids in the lysosomal compartment, and such defects are the basis of NPC disease. Several parallels exist between NPC disease and Alzheimers disease (AD), including altered cholesterol homeostasis, changes in the lysosomal system, neurofibrillary tangles, and increased amyloid-beta generation. How the expression of NPC1 in the human brain is affected in AD has not been investigated so far. In the present study, we measured NPC1 mRNA and protein expression in three distinct regions of the human brain, and we revealed that NPC1 expression is upregulated at both mRNA and protein levels in the hippocampus and frontal cortex of AD patients compared to control individuals. In the cerebellum, a brain region that is relatively spared in AD, no difference in NPC1 expression was detected. Similarly, murine NPC1 mRNA levels were increased in the hippocampus of 12-month-old transgenic mice expressing a familial AD form of human amyloid-beta precursor protein (APP) and presenilin-1 (APP/PS1tg) compared to 12-month-old wild type mice, whereas no change in NPC1 was detected in mouse cerebellum. Immunohistochemical analysis of human hippocampus indicated that NPC1 expression was strongest in neurons. However, in vitro studies revealed that NPC1 expression was not induced by transfecting SK-N-SH neurons with human APP or by treating them with oligomeric amyloid-beta peptide. Total cholesterol levels were reduced in hippocampus from AD patients compared to control individuals, and it is therefore possible that the increased expression of NPC1 is linked to perturbed cholesterol homeostasis in AD.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2010
Keywords
Alzheimers disease; Niemann-Pick; Cholesterol; Lysosome; CA1; Hippocampus; Cerebellum; Frontal cortex
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-58275 (URN)10.1016/j.bbalip.2010.05.005 (DOI)000279476000012 ()
Available from: 2010-08-10 Created: 2010-08-09 Last updated: 2017-12-12
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