We propose to integrate molecular biology, morphometry, and clinical studies to identify mechanisms leading to abnormal brain development, accelerated aging, and early onset of Alzheimer disease in people with Down syndrome (DS). We plan to conduct biochemical and morphometric studies of the memory system (hippocampus, amygdala, and entorhinal cortex) and sensory-motor system ( substantia nigra, pedunculopontine tegmental nucleus, caudal intralaminar thalamus, caudate nucleus, putamen, globus pallidus, nucleus accumbens, motor cortex, and cerebellum) in 44 people with DS. Because all people with DS develop early onset AD and some develop parkinsonian-type neurodegeneration, the mechanisms of neuronal loss in DS will be compared with temporal and topographic patterns of neuronal degeneration and loss in sporadic AD (30 cases), idiopathic PD (30 cases), and normal aging (44 cases). Our goal will be to determine: (1) the role of abnormal expression of Mnbk/DyrklA in developmental neuronal deficits in the memory and motor system of people with DS; (2) the mechanisms of synaptic abnormalities caused by excess of Mnbk/Dyrk1A protein in people with DS; (3) the role of Mnbk/Dyrk1A protein in brain accelerated aging during the fourth decade of life in people with DS; (4) the contribution of different mechanisms of neurodegeneration to dementia and motor deterioration in people with DS over 40 years of age; (5) modifications in the contribution of neurodegenerative changes to neuronal and functional loss in people with DS in comparison to normal aging, sporadic AD, and idiopathic PD. We hypothesize that in DS the extra copy of the Mnbk/Dyrk1A gene is not only a key factor in shaping structural and functional developmental abnormalities, but also affects the function of synapses in adulthood, contributes to accelerating aging of the brain, and changes the structural and functional background for development of AD and PD pathology. We hypothesize that we will be able to identify DS-specific modifications of the course of AD and PD pathology. This study will provide a foundation for identifying the mechanisms and morphological substrate of specific functional deficits, and should contribute to the improvement of diagnosis and treatment.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD043960-05
Application #
7392658
Study Section
Brain Disorders and Clinical Neuroscience 5 (BDCN)
Program Officer
Oster-Granite, Mary Lou
Project Start
2004-01-01
Project End
2010-12-31
Budget Start
2008-01-01
Budget End
2010-12-31
Support Year
5
Fiscal Year
2008
Total Cost
$521,790
Indirect Cost
Name
Institute for Basic Research in Dev Disabil
Department
Type
DUNS #
167205090
City
Staten Island
State
NY
Country
United States
Zip Code
10314
Kaczmarski, Wojciech; Barua, Madhabi; Mazur-Kolecka, Bozena et al. (2014) Intracellular distribution of differentially phosphorylated dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). J Neurosci Res 92:162-73
Xie, Wen; Adayev, Tatyana; Zhu, Huiyuan et al. (2012) Activity-dependent phosphorylation of dynamin 1 at serine 857. Biochemistry 51:6786-96
Dowjat, Karol; Adayev, Tatyana; Kaczmarski, Wojciech et al. (2012) Gene dosage-dependent association of DYRK1A with the cytoskeleton in the brain and lymphocytes of down syndrome patients. J Neuropathol Exp Neurol 71:1100-12
Wegiel, Jerzy; Frackowiak, Janusz; Mazur-Kolecka, Bozena et al. (2012) Abnormal intracellular accumulation and extracellular A? deposition in idiopathic and Dup15q11.2-q13 autism spectrum disorders. PLoS One 7:e35414
Wegiel, Jerzy; Kaczmarski, Wojciech; Barua, Madhabi et al. (2011) Link between DYRK1A overexpression and several-fold enhancement of neurofibrillary degeneration with 3-repeat tau protein in Down syndrome. J Neuropathol Exp Neurol 70:36-50
Wegiel, Jerzy; Gong, Cheng-Xin; Hwang, Yu-Wen (2011) The role of DYRK1A in neurodegenerative diseases. FEBS J 278:236-45
Adayev, Tatyana; Wegiel, Jerzy; Hwang, Yu-Wen (2011) Harmine is an ATP-competitive inhibitor for dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A). Arch Biochem Biophys 507:212-8
Miller, David L; Potempska, Anna; Wegiel, Jerzy et al. (2011) High-affinity rabbit monoclonal antibodies specific for amyloid peptides amyloid-ýý40 and amyloid-ýý42. J Alzheimers Dis 23:293-305
Wegiel, Jerzy; Kuchna, Izabela; Nowicki, Krzysztof et al. (2010) The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changes. Acta Neuropathol 119:755-70
Ji, Lina; Chauhan, Abha; Wegiel, Jerzy et al. (2009) Gelsolin is proteolytically cleaved in the brains of individuals with Alzheimer's disease. J Alzheimers Dis 18:105-11

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