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Lack of Neuronal IFN-?-IFNAR Causes Lewy Body- and Parkinson's Disease-like Dementia.

ABSTRACT: Neurodegenerative diseases have been linked to inflammation, but whether altered immunomodulation plays a causative role in neurodegeneration is not clear. We show that lack of cytokine interferon-? (IFN-?) signaling causes spontaneous neurodegeneration in the absence of neurodegenerative disease-causing mutant proteins. Mice lacking Ifnb function exhibited motor and cognitive learning impairments with accompanying ?-synuclein-containing Lewy bodies in the brain, as well as a reduction in dopaminergic neurons and defective dopamine signaling in the nigrostriatal region. Lack of IFN-? signaling caused defects in neuronal autophagy prior to ?-synucleinopathy, which was associated with accumulation of senescent mitochondria. Recombinant IFN-? promoted neurite growth and branching, autophagy flux, and ?-synuclein degradation in neurons. In addition, lentiviral IFN-? overexpression prevented dopaminergic neuron loss in a familial Parkinson's disease model. These results indicate a protective role for IFN-? in neuronal homeostasis and validate Ifnb mutant mice as a model for sporadic Lewy body and Parkinson's disease dementia.

SUBMITTER: Ejlerskov P

PROVIDER: S-EPMC4601085 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Lack of Neuronal IFN-β-IFNAR Causes Lewy Body- and Parkinson's Disease-like Dementia.

Ejlerskov Patrick P Hultberg Jeanette Göransdotter JG Wang JunYang J Carlsson Robert R Ambjørn Malene M Kuss Martin M Liu Yawei Y Porcu Giovanna G Kolkova Kateryna K Friis Rundsten Carsten C Ruscher Karsten K Pakkenberg Bente B Goldmann Tobias T Loreth Desiree D Prinz Marco M Rubinsztein David C DC Issazadeh-Navikas Shohreh S

Cell 20151001 2

Neurodegenerative diseases have been linked to inflammation, but whether altered immunomodulation plays a causative role in neurodegeneration is not clear. We show that lack of cytokine interferon-β (IFN-β) signaling causes spontaneous neurodegeneration in the absence of neurodegenerative disease-causing mutant proteins. Mice lacking Ifnb function exhibited motor and cognitive learning impairments with accompanying α-synuclein-containing Lewy bodies in the brain, as well as a reduction in dopami ...[more]

PMID: 26451483

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Project description:BackgroundParkinson's disease (PD) is a condition that affects movement and is usually seen in those over the age of 50. It is caused by the death of dopaminergic neurons, particularly in the substantia nigra. PD has shifted from being perceived as an uncommon condition to a significant neurological illness, mostly due to the increasing number of elderly individuals and the impact of environmental factors. Parkinson's plus syndromes, such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal degeneration (CBD), and vascular Parkinsonism (VaP), provide difficulties in distinguishing them clinically from PD since they have similar characteristics.MethodologyA thorough examination was performed utilizing the PubMed, Medline, Scopus, and Web of Science databases. The search utilized specific keywords like "Parkinson's disease," "Parkinson's plus syndrome," "Lewy body dementia," "Alzheimer's dementia," "progressive supranuclear palsy," and "multiple system atrophy." The selection criteria were aimed at English-language literature, with a particular focus on examining the connection between PD and associated disorders or dementias.Results and discussionParkinson's plus syndromes, such as PSP, MSA, CBD, and VaP, exhibit unique clinical characteristics, imaging results, and diverse reactions to levodopa. This makes it difficult to distinguish them from PD. LBD is characterized by Lewy bodies containing α-synuclein, which leads to both motor and cognitive deficits. PD and Alzheimer's disease (AD) exhibit a complex interaction, including common pathogenic processes, genetic predispositions, and clinical characteristics of dementia.ConclusionThe interrelatedness of PD, Parkinson's plus syndromes, LBD, and AD highlights the significance of comprehending shared disease-causing processes. Aberrant protein clumping, impaired functioning of mitochondria, increased oxidative stress, and inflammation in the brain are common factors which can be addressed for specific treatments. More research is essential for understanding complicated connections and developing effective therapies for these sophisticated neurological illnesses.

Project description:As the differential diagnosis of dementias based on established clinical criteria is often difficult, biomarkers for applicable diagnostic testing are currently under intensive investigation. Amyloid plaques deposited in the brain of patients suffering from Alzheimer's disease, dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) mainly consist of carboxy-terminally elongated forms of amyloid-beta (Abeta) peptides, such as Abeta1-42. Absolute Abeta1-42 levels in CSF have shown diagnostic value for the diagnosis of Alzheimer's disease, but the discrimination among Alzheimer's disease, DLB and PDD was poor. A recently established quantitative urea-based Abeta-sodium-dodecylsulphate-polyacrylamide-gel-electrophoresis with Western immunoblot (Abeta-SDS-PAGE/immunoblot) revealed a highly conserved Abeta peptide pattern of the carboxy-terminally truncated Abeta peptides 1-37, 1-38, 1-39 in addition to 1-40 and 1-42 in human CSF. We used the Abeta-SDS-PAGE/immunoblot to investigate the CSF of 23 patients with Alzheimer's disease, 21 with DLB, 21 with PDD and 23 non-demented disease controls (NDC) for disease-specific alterations of the Abeta peptide patterns in its absolute and relative quantities. The diagnostic groups were matched for age and severity of dementia. The present study is the first attempt to evaluate the meaning of Abeta peptide patterns in CSF for differential diagnosis of the three neurodegenerative diseases--Alzheimer's disease, DLB and PDD. The Abeta peptide patterns displayed disease-specific variations and the ratio of the differentially altered Abeta1-42 to the Abeta1-37 levels subsequently discriminated all diagnostic groups from each other at a highly significant level, except DLB from PDD. Additionally, a novel peptide with Abeta-like immunoreactivity was observed constantly in the CSF of all 88 investigated patients. The pronounced percentage increase of this peptide in DLB allowed a highly significant discrimination from PDD. Using a cut-off point of 0.954%, this marker yielded a diagnostic sensitivity and specificity of 81 and 71%, respectively. From several lines of indication, we consider this peptide to represent an oxidized alpha-helical form of Abeta1-40 (Abeta1-40*). The increased abundance of Abeta1-40* probably reflects a disease-specific alteration of the Abeta1-40 metabolism in DLB. We conclude that Abeta peptide patterns reflect disease-specific pathophysiological pathways of different dementia syndromes as distinct neurochemical phenotypes. Although Abeta peptide patterns failed to fulfil the requirements for a sole biomarker, their combined evaluation with other biomarkers is promising in neurochemical dementia diagnosis. It is noteworthy that DLB and PDD exhibit distinct clinical temporal courses, despite their similar neuropathological appearance. Their distinct molecular phenotypes support the view of different pathophysiological pathways for each of these neurodegenerative diseases.

Dataset Information

Lack of Neuronal IFN-?-IFNAR Causes Lewy Body- and Parkinson's Disease-like Dementia.

Publications

Lack of Neuronal IFN-β-IFNAR Causes Lewy Body- and Parkinson's Disease-like Dementia.

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