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Lipocalin 2 and its receptor, megalin, as diagnostic and drug targets in early stages of Alzheimer’s disease.

Projectomschrijving

Ons eerdere werk heeft geleid tot de identificatie van een ontstekingseiwit genaamd Lipocaline-2 (Lcn2) in de ziekte van Alzheimer (ALZ).

Doel

Het huidige project onderzocht of Lcn2 geschikt is als biomarker voor het vroegtijdig detecteren van ALZ en behandeling van ALZ in een vroeg stadium.

Aanpak

Lcn2 niveaus in het bloed en hersenvocht van oudere deelnemers van verschillende longitudinale onderzoeken bleken afwijkende Lcn2 niveaus in het hersenvocht voorspellend te zijn voor de conversie van een milde cognitive stoornis naar Alz twee jaar later. Lcn2 zou daarnaast nut kunnen hebben voor het onderscheid tussen Alz en andere vormen van dementie.

Resultaten

Er werd een medicament gevonden dat Lcn2 niveaus verlaagde in celculturen van hersencellen. Nader onderzoek in muizen toonde aan dat dit medicament Lcn2 niveaus en Alz pathologie verminderde. De bevindingen ondersteunen dat Lcn2 een veelbelovende biomarker is voor de vroegdetectie van Alz en daarbij een therapeutisch aangrijpingspunt zou kunnen zijn.

Meer informatie

Producten

Titel: Lipocalin 2 and the pathophysiology of Alzheimer's disease
Auteur: Prof. Peter Paul De Deyn, Prof. Ulrich M. Eisel, Dr. Pieter Naudé
Titel: Dynamics of neutrophil gelatinase-associated lipocalin plasma and cerebrospinal fluid concentrations in older males
Auteur: Naudé, Petrus J. W., Dekens, Doortje W., Eisel, Ulrich L. M., den Daas, Izaak, De Deyn, Peter P.
Magazine: European Journal of Clinical Investigation
Titel: Neutrophil Gelatinase-Associated Lipocalin and its Receptors in Alzheimer's Disease (AD) Brain Regions: Differential Findings in AD with and without Depression.
Auteur: Dekens, Doortje W., Naudé, Petrus J.W., Engelborghs, Sebastiaan, Vermeiren, Yannick, Van Dam, Debby, Oude Voshaar, Richard C., Eisel, Ulrich L.M., De Deyn, Peter P.
Magazine: Journal of Alzheimer's disease
Titel: Lipocalin 2 contributes to brain iron dysregulation but does not affect cognition, plaque load, and glial activation in the J20 Alzheimer mouse model
Auteur: Dekens, Doortje W., Naudé, Petrus J. W., Keijser, Jan N., Boerema, Ate S., De Deyn, Peter P., Eisel, Ulrich L. M.
Magazine: Journal of Neuroinflammation
Titel: Serum and cerebrospinal fluid Neutrophil gelatinase-associated lipocalin (NGAL) levels as biomarkers for the conversion from mild cognitive impairment to Alzheimer's disease dementia
Auteur: Petrus J W Naudé, Inez H G B Ramakers, Wiesje M van der Flier , Lize C Jiskoot, Fransje E Reesink, Jurgen A H R Claassen, Huiberdina L Koek, Ulrich L M Eisel, Peter P De Deyn
Magazine: Neurobiology of Aging
Titel: Iron Chelators Inhibit amyloid-ß-induced Production of Lipocalin 2 in Cultured Astrocytes
Auteur: Dekens DW, De Deyn PP, Sap F, Eisel ULM, and Naudé PJ
Magazine: Neurochemical International
Titel: Lipocalin 2 as a link between ageing, risk factor conditions and age-related brain diseases
Auteur: Doortje W Dekens, Ulrich L M Eisel, Leonie Gouweleeuw, Regien G Schoemaker, Peter P De Deyn, Petrus J W Naudé
Magazine: Ageing Research Reviews

Verslagen


Samenvatting van de aanvraag

Alzheimer’s disease (AD) is a complex multifactorial neurodegenerative disorder characterized by loss of memory and severe impairment of cognitive abilities. It is predicted that AD will become an imminent global epidemic in the near future if necessary preventative processes are not undertaken in time (1). For more than a century, research primarily focused on the classical neuropathological hallmarks of AD which are extracellular accumulation of aggregated amyloid beta (AB) deposits (amyloid hypothesis of AD) and, neurofibrillary tangles of phosphorylated tau protein in dead and dying neurons (tau hypothesis of AD) (2). Attempts towards treatment of this devastating disease often focused on a single aspect of these hypotheses and, as such, have remained unsuccessful. It is now recognized that the disease is progressing in a much more complex manner and that other factors than tau or AB accumulation play a role. For example, an abnormal immune response, characterized by a pro-inflammatory environment, was more recently identified as a fundamental feature in AD development (3, 4). Study of inflammation in AD appears of particular importance since it occurs in early phases of the disease, which opens promising avenues for diagnostic and therapeutic developments. This project introduces Lipocalin 2 (Lcn2) as novel (neuro)inflammatory component of the early stages of AD development. Lcn2, also known as NGAL, is a 25 kDa acute phase protein and primarily functions as an anti-bacterial agent (5). In the brain, Lcn2 mRNA and protein expression levels are very low under physiological conditions (6, 7). Lcn2 can be produced by several cells in the brain, including neurons, microglial cells, endothelial cells and especially astrocytes during pro-inflammatory conditions (8, 9). Lcn2 acts via its two receptors: megalin (10) and 24p3R (11). Interestingly, megalin also functions as a transporter of the blood brain barrier (BBB) and blood-CSF barrier and is involved in the efflux of AB and possibly Lcn2 out of the brain. The role of Lcn2 in AD was first described about three and a half years ago, as part of my PhD project (8). The following data obtained during my PhD and postdoc, together with some recent findings from other research groups, strongly indicate that Lcn2 and its receptors, particularly megalin, play important roles in the disease development of AD (see Fig. 1 in the attachment). Blood Lcn2 levels in AD and risk factors for AD: Systemic Lcn2 levels increase with age (12) and age the greatest known risk factor for AD. Blood Lcn2 levels are increased in patients with Mild Cognitive Impairment (MCI), AD patients (8, 13) and in depressed older persons (12). In addition, we found that increased blood Lcn2 is associated with impaired recall memory in females with late-life depression (14). This is of interest because depression in the elderly is an know risk factor for AD, especially with co-existing impaired recall memory, which is largely dependent on hippocampus functioning (15). Lcn2 expression in AD brain: In post mortem human AD brain tissue, we found a robust increase in Lcn2 expression with a similar regional distribution pattern as AD pathology, particularly in the hippocampus (8). CSF Lcn2 levels in MCI and AD and the role of megalin in Lcn2 regulation: Contrary to other inflammatory proteins, Lcn2 is robustly decreased in the cerebrospinal fluid (CSF) of MCI patients (whom later converted to AD) and AD patients, compared to healthy elderly people (8). Decreased Lcn2 corresponds to findings showing decreased CSF AB42 levels in AD (16). In this regard, megalin is a receptor for Lcn2 (10) and transports AB42 out of the brain across the blood-CSF barrier (17). Because megalin is decreased on the brain-CSF barrier in human AD patients (18), it can result in decreased transport of Lcn2 and AB42 out of the brain, resulting in increased brain and decreased CSF levels. Interestingly, an BBB megalin deficient mouse model developed memory impairments and neuronal death, similar to an AD mouse model (19). Role of increased Lcn2 in AD pathology: Lcn2 sensitizes neurons to the toxic effects of oligomeric forms of AB(42) (8). Elevated Lcn2 shifts neuroprotective to pro-apoptotic mechanisms by inhibiting the PKB/Akt pathway (8) and impairing neuroplasticity and hippocampal neuronal growth (7). Increased Lcn2 induces astrocytes and microglia to a pro-inflammatory phenotype and silences their neuroprotective anti-inflammatory functioning (20, 21), whereas elimination of Lcn2 reduces neuroinflammation and neuronal damage during neuronal injury (22). This project will investigate the functions of Lcn2 and megalin in the pathophysiology of AD and their potential uses as diagnostic and therapeutic targets for early AD, addressing two fundamental research topics in this field: i.e. early diagnosis and early intervention, aiming to prevent AD development or at least stop or slow down the disease progression.

Kenmerken

Projectnummer:
733050501
Looptijd: 100%
Looptijd: 100 %
2015
2021
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Dr. P.J.W. Naudé
Verantwoordelijke organisatie:
Universitair Medisch Centrum Groningen