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

Abstract

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 spindown 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.

Proteomics Study of Peripheral Blood Mononuclear Cells in Down Syndrome Children

“…Published studies showed that both brain tissue and immortalized lymphocytes of DS patients displayed a significant reduction in the yield of all the major cytoskeletal proteins co-immunoprecipitated with DYRK1A antibodies [ 101 ]. Similarly to DS cells, overexpression of DYRK1A in trisomic TgDYRK1A mice was shown to cause alterations in actin dynamic through increased stability of actin filaments [ 102 ]. Further, results from Ori-McKenney et al demonstrated that the regulation of microtubule dynamics by DYRK1A-mediated phosphorylation is critical for dendritic patterning and neuronal function, revealing a previously unidentified mode of post-translational microtubule regulation in neurons and uncovering a conserved pathway for a DS-associated kinase [ 100 ].…”

Body Fluid Biomarkers for Alzheimer’s Disease—An Up-To-Date Overview

“…On the other hand, DYRK1A, a member of the proline-directed serine/threonine kinases, is widely known for its implications for cell proliferation, as well as various signaling pathways fundamental for brain development and function, namely neuron survival, synaptic plasticity, and actin cytoskeleton and microtubule regulation [ 119 , 120 , 121 ]. As AD patients present considerably reduced blood levels, DYRK1A could be used as a potential biomarker [ 105 , 122 ].…”

Regeneration of Pancreatic β-Cells for Diabetes Therapeutics by Natural DYRK1A Inhibitors

“…DYRK1A is a potential therapeutic target for many diseases including Down Syndrome (DS) [ 30 , 31 ], Alzheimer’s disease (AD) [ 32 , 33 ] and Parkinson’s disease (PD) [ 34 ]. DYRK1A also plays an important role in the survival and proliferation of many tumor cells [ 35 , 36 , 37 ].…”