Increased Cerebrospinal Fluid Levels of Ubiquitin Carboxyl-Terminal Hydrolase L1 in Patients with Alzheimer's Disease

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Abstract

Background: Dysfunctions of the ubiquitin proteasome system (UPS), including the highly abundant neuronal enzyme ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), and autophagy-related changes (lysosomal degradation) are implicated in several neurodegenerative disorders including Alzheimer's disease (AD). Method: This study evaluated cerebrospinal fluid (CSF) levels of UCH-L1, protein deglycase (DJ-1), neuron-specific enolase (NSE), and tau phosphorylated at threonine 231 (P-tau<sub>231</sub>) in two independent patient and control cohorts. Cohort 1 included CSF samples from subjects having an AD biomarker profile (n = 10) or a control biomarker profile (n = 31), while cohort 2 was a monocenter clinical study including patients with AD (n = 32), mild cognitive impairment (n = 13), other dementias (n = 15), as well as cognitively healthy controls (n = 20). Results: UCH-L1 and P-tau<sub>231</sub> were elevated in AD patients compared to controls in both cohorts. CSF levels of DJ-1 and NSE were unchanged in the AD group, whereas they were decreased in the group of other dementia compared to controls in the clinical study. Conclusion: Our main findings support that the UPS pathway may be impaired in AD, and UCH-L1 may serve as an additional CSF biomarker for AD.

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Alzheimer's disease.

Kaj Blennow, Mony J. de Leon, Henrik Zetterberg (2006)

Alzheimer's disease is the most common cause of dementia. Research advances have enabled detailed understanding of the molecular pathogenesis of the hallmarks of the disease--ie, plaques, composed of amyloid beta (Abeta), and tangles, composed of hyperphosphorylated tau. However, as our knowledge increases so does our appreciation for the pathogenic complexity of the disorder. Familial Alzheimer's disease is a very rare autosomal dominant disease with early onset, caused by mutations in the amyloid precursor protein and presenilin genes, both linked to Abeta metabolism. By contrast with familial disease, sporadic Alzheimer's disease is very common with more than 15 million people affected worldwide. The cause of the sporadic form of the disease is unknown, probably because the disease is heterogeneous, caused by ageing in concert with a complex interaction of both genetic and environmental risk factors. This seminar reviews the key aspects of the disease, including epidemiology, genetics, pathogenesis, diagnosis, and treatment, as well as recent developments and controversies.

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Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop.

G C Román, T K Tatemichi, T Erkinjuntti … (1993)

Criteria for the diagnosis of vascular dementia (VaD) that are reliable, valid, and readily applicable in a variety of settings are urgently needed for both clinical and research purposes. To address this need, the Neuroepidemiology Branch of the National Institute of Neurological Disorders and Stroke (NINDS) convened an International Workshop with support from the Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN), resulting in research criteria for the diagnosis of VaD. Compared with other current criteria, these guidelines emphasize (1) the heterogeneity of vascular dementia syndromes and pathologic subtypes including ischemic and hemorrhagic strokes, cerebral hypoxic-ischemic events, and senile leukoencephalopathic lesions; (2) the variability in clinical course, which may be static, remitting, or progressive; (3) specific clinical findings early in the course (eg, gait disorder, incontinence, or mood and personality changes) that support a vascular rather than a degenerative cause; (4) the need to establish a temporal relationship between stroke and dementia onset for a secure diagnosis; (5) the importance of brain imaging to support clinical findings; (6) the value of neuropsychological testing to document impairments in multiple cognitive domains; and (7) a protocol for neuropathologic evaluations and correlative studies of clinical, radiologic, and neuropsychological features. These criteria are intended as a guide for case definition in neuroepidemiologic studies, stratified by levels of certainty (definite, probable, and possible). They await testing and validation and will be revised as more information becomes available.

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DJ-1 has a role in antioxidative stress to prevent cell death.

Takahiro Taira, Yoshiro Saito, Takeshi Niki … (2004)

Deletion and point (L166P) mutations of DJ-1 have recently been shown to be responsible for the onset of familial Parkinson's disease (PD, PARK7). The aim of this study was to determine the role of DJ-1 in PD. We first found that DJ-1 eliminated hydrogen peroxide in vitro by oxidizing itself. We then found that DJ-1 knockdown by short interfering RNA rendered SH-SY5Y neuroblastoma cells susceptible to hydrogen peroxide-, MPP+- or 6-hydroxydopamine-induced cell death and that cells harbouring mutant forms of DJ-1, including L166P, became susceptible to death in parallel with the loss of oxidized forms of DJ-1. These results clearly showed that DJ-1 has a role in the antioxidative stress reaction and that mutations of DJ-1 lead to cell death, which is observed in PD.

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Author and article information

Journal

Journal ID (publisher-id): DEE

Journal ID (pmc): DEE

Journal ID (doi): 10.1159/issn.1664-5464

Title: Dementia and Geriatric Cognitive Disorders Extra

Publisher: S. Karger AG

ISSN (Electronic): 1664-5464

Publication date Subscription-year: 2016

Publication date Collection: May – August 2016

Publication date (Electronic): 15 July 2016

Volume: 6

Issue: 2

Pages: 283-294

Affiliations

^aClinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska University Hospital Mölndal, Sahlgrenska Academy, University of Gothenburg, Mölndal, ^bDepartment of Neuropsychiatry, Skaraborg Hospital, Falköping, ^cDepartment of Endocrinology, Skaraborg Hospital, Skövde, and ^dInstitute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; ^eUCL Institute of Neurology, London, UK

Author notes

*Annika Öhrfelt, Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska University Hospital Mölndal, Sahlgrenska Academy, University of Gothenburg, SE-431 80 Mölndal (Sweden), E-Mail annika.ohrfelt@neuro.gu.se

Article

Publisher ID: 447239 Pmcid ID: PMC4965532 Other ID: Dement Geriatr Cogn Disord Extra 2016;6:283-294

DOI: 10.1159/000447239

PMC ID: PMC4965532

PubMed ID: 27504117

SO-VID: 4e412e2c-49ac-43cb-9cdd-99233c64bc0d

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Increased Cerebrospinal Fluid Levels of Ubiquitin Carboxyl-Terminal Hydrolase L1 in Patients with Alzheimer's Disease

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Abstract

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Karger: Neurology and Neuroscience

Most cited references 40

Alzheimer's disease.

Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop.

DJ-1 has a role in antioxidative stress to prevent cell death.

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Cited by 20

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