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Autotaxin and Glutamate Dysregulation in Alzheimer's Mice Model
Author(s) -
Jones Ellery,
Govindarajulu Manoj,
Knowlton Stella,
Suppiramaniam Vishnu
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.552.7
Subject(s) - autotaxin , glutamate receptor , insulin resistance , hippocampus , medicine , synaptic plasticity , neuroscience , lysophosphatidic acid , endocrinology , biology , diabetes mellitus , receptor
Without the development of new therapeutics, the number of cases of Alzheimer's disease (AD) – currently estimated to be greater than 5.4 million – will rapidly increase in the coming decades. As well, the total estimated worldwide cost of dementia is US$818 billion, according to World Alzheimer's Report 2016. Current treatments provide, at best, only modest and temporary symptomatic relief, failing to alter the underlying pathophysiology, which leads to the onset and mediates the progression of the disease. Autotaxin, is an adipokine that is upregulated in type 2 diabetes mellitus and obesity, indicating a potential involvement of insulin resistance. Mounting evidence suggests that hyperactivation of the Autotaxin (ATX) pathway helps drive neurologic dysfunction in Alzheimer's disease (AD). The deleterious effects of Autotaxin activity on neuronal function appear to be strongly linked to the dysregulation of glutamate homeostasis. The goals of the proposed research were to test the involvement of the Autotaxin (ATX) pathway in glutamate dysregulation associated with AD. We utilized intracerebroventricular (ICV) Streptozotocin (STZ) treated mice to induce brain insulin resistance at 2 months of age and compared with control mice. Autotaxin levels in the hippocampus and cortex were quantified by performing western blot and rt‐PCR, measuring autotaxin mRNA at 4, 8 and 12 months of age. Behavioral studies and electrophysiological studies were performed to assess the cognitive deficits. Finally, biochemical assays to quantify levels of glutamate transporters, other glutamate regulatory proteins, expression of PSD‐95 and Arc proteins essential for synaptic maturity and plasticity and P38 MAPkinase were conducted with hippocampal and cortical lysates. Compared with controls, STZ mice showed significant memory impairment, reduction of synaptic long‐term potentiation and decreased synaptic proteins, which were mediated by the activation of the P38 MAPK Kinase pathway. We believe our studies demonstrate, for the first time, that an increase in autotaxin in the central nervous system directly triggers behavioral and cognitive deficits by promoting synaptic dysfunction, thereby uncovering the molecular mechanisms of autotaxin‐regulated glutamate dyshomeostasis in AD, and possibly other neurodegenerative disorders. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .