Abnormalities of DYRK1A-Cytoskeleton Complexes in the Blood Cells as Potential Biomarkers of Alzheimer’s Disease

Autor: Urszula Wojda, Tatyana Adayev, Tomasz Gabryelewicz, Anna Barczak, Katarzyna Brzozowska, Karol Dowjat, Yu-Wen Hwang
Rok vydání: 2019
Předmět:
Male
0301 basic medicine
Pathology
DYRK1A
AD biomarkers
Down syndrome
diagnostic tests in blood cells
0302 clinical medicine
Cytoskeleton
Aged
80 and over
General Neuroscience
Actin cytoskeleton
General Medicine
Middle Aged
Protein-Tyrosine Kinases
3. Good health
Psychiatry and Mental health
Clinical Psychology
Biomarker (medicine)
Female
medicine.symptom
Alzheimer’s disease
Research Article
Adult
medicine.medical_specialty
Adolescent
Protein Serine-Threonine Kinases
Asymptomatic
Cell Line
Young Adult
03 medical and health sciences
Alzheimer Disease
medicine
Humans
Immunoprecipitation
Dementia
Cognitive Dysfunction
Actin
Aged
business.industry
medicine.disease
Actins
030104 developmental biology
Leukocytes
Mononuclear
Geriatrics and Gerontology
business
Biomarkers
030217 neurology & neurosurgery
Zdroj: Journal of Alzheimer's Disease
ISSN: 1875-8908
1387-2877
DOI: 10.3233/jad-190475
Popis: Background DYRK1A is implicated in mental retardation and Alzheimer's disease (AD) dementia of Down syndrome (DS) individuals. The protein is associated with cytoskeleton and altered expression has been shown to impair the cytoskeletal network via dosage effect. Objective Our original observations of marked reduction of cytoskeletal proteins associated with DYRK1A in brains and lymphoblastoid cell lines from DS and AD prompted an investigation whether cytoskeleton abnormalities could potentially be used as biomarkers of AD. Methods Our assay relied on quantification of co-immunoprecipitated cytoskeletal proteins with DYRK1A (co-IP assay) and analysis of the profile of G- and F-actin fractions obtained by high-speed centrifugations (spin-down assay). Results In co-IP assay, both DS and AD samples displayed reduced abundance of associated cytoskeletal proteins. In spin-down assay, G-actin fractions of controls displayed two closely spaced bands of actin in SDS-PAGE; while in AD and DS, only the upper band of the doublet was present. In both assays, alterations of actin cytoskeleton were present in DS, sporadic and familial AD cases, and in asymptomatic persons who later progressed to confirmed AD, but not in non-AD donors. In blind testing involving six AD and six controls, the above tests positively identified ten cases. Analysis of blood samples revealed the diversity of mild cognitive impairment (MCI) cases regarding the presence of the AD biomarker allowing distinction between likely prodromal AD and non-AD MCI cases. Conclusions Both brain tissue and lymphocytes from DS and AD displayed similar semi-quantitative and qualitative alterations of actin cytoskeleton. Their specificity for AD-type dementia and the presence before clinical onset of the disease make them suitable biomarker candidates for early and definite diagnosis of AD. The presence of alterations in peripheral tissue points to systemic underlying mechanisms and suggests that early dysfunction of cytoskeleton may be a predisposing factor in the development of AD.
Databáze: OpenAIRE
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