Singh, BK and Vatsa, N and Kumar, V and Shekhar, S and Sharma, A and Jana, NR (2017) Ube3a deficiency inhibits amyloid plaque formation in APPswe/PS1δE9 mouse model of Alzheimer's disease. Human Molecular Genetics, 26 (20). pp. 4042-4054.

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Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive decline in memory and cognitive function. Pathological hallmark of AD includes aberrant aggregation of amyloid beta (Aβ) peptide, which is produced upon sequential cleavage of amyloid precursor protein (APP) by β- and γ -secretases. On the contrary, α-secretase cleaves APP within the Aβ sequence and thereby prevents Aβ generation. Here, we investigated the role of ubiquitin ligase Ube3a (involved in synaptic function and plasticity) in the pathogenesis of AD using APPswe/PS1δE9 transgenic mouse model and first noticed that soluble pool of Ube3a was age-dependently decreased in AD mouse in comparison with wild type controls. To further explore the role of Ube3a in AD patho-mechanism, we generated brain Ube3a-deficient AD mice that exhibited accelerated cognitive and motor deficits compared with AD mice. Interestingly, these Ube3a-deficient AD mice were excessively obese from their age of 12 months and having shorter lifespan. Biochemical analysis revealed that the Ube3a-deficient AD mice had significantly reduced level of Aβ generation and amyloid plaque formation in their brain compared with age-matched AD mice and this effect could be due to the increased activity of α-secretase, ADAM10 (a disintegrin and metalloproteinase-10) that shift the proteolysis of APP towards non-amyloidogenic pathway. These findings suggest that aberrant function of Ube3a could influence the progression of AD and restoring normal level of Ube3a might be beneficial for AD.

Item Type:	Article
Subjects:	Neurodegenerative Disorders Neuro-Oncological Disorders Neurocognitive Processes Neuronal Development and Regeneration Informatics and Imaging Genetics and Molecular Biology
Depositing User:	Dr. D.D. Lal
Date Deposited:	11 Jan 2018 08:42
Last Modified:	18 May 2018 10:19
URI:	http://nbrc.sciencecentral.in/id/eprint/316

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