Gad67 haploinsufficiency reduces amyloid pathology and rescues olfactory memory deficits in a mouse model of Alzheimer's disease

Yue Wang, Zheng Wu, Yu-Ting Bai, Gang-Yi Wu, Gong Chen
<span title="2017-10-10">2017</span> <i title="Springer Nature"> <a target="_blank" rel="noopener" href="" style="color: black;">Molecular Neurodegeneration</a> </i> &nbsp;
Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder, affecting millions of people worldwide. Although dysfunction of multiple neurotransmitter systems including cholinergic, glutamatergic and GABAergic systems has been associated with AD progression the underlying mechanisms remain elusive. We and others have recently found that GABA content is elevated in AD brains and linked to cognitive deficits in AD mouse models. The glutamic acid decarboxylase 67 (GAD67) is
more &raquo; ... he major enzyme converting glutamate into GABA and has been implied in a number of neurological disorders such as epilepsy and schizophrenia. However, whether Gad67 is involved in AD pathology has not been well studied. Here, we investigate the functional role of GAD67 in an AD mouse model with Gad67 haploinsufficiency that is caused by replacing one allele of Gad67 with green fluorescent protein (GFP) gene during generation of GAD67-GFP mice. Methods: To genetically reduce GAD67 in AD mouse brains, we crossed the Gad67 haploinsufficient mice (GAD67-GFP +/− ) with 5xFAD mice (harboring 5 human familial AD mutations in APP and PS1 genes) to generate a new line of bigenic mice. Immunostaining, ELISA, electrophysiology and behavior test were applied to compare the difference between groups. Results: We found that reduction of GAD67 resulted in a significant decrease of amyloid β production in 5xFAD mice. Concurrently, the abnormal astrocytic GABA and tonic GABA currents, as well as the microglial reactivity were significantly reduced in the 5xFAD mice with Gad67 haploinsufficiency. Importantly, the olfactory memory deficit of 5xFAD mice was rescued by Gad67 haploinsufficiency. Conclusions: Our results demonstrate that GAD67 plays an important role in AD pathology, suggesting that GAD67 may be a potential drug target for modulating the progress of AD.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="">doi:10.1186/s13024-017-0213-9</a> <a target="_blank" rel="external noopener" href="">pmid:29017573</a> <a target="_blank" rel="external noopener" href="">pmcid:PMC5633901</a> <a target="_blank" rel="external noopener" href="">fatcat:prybip3hq5hcrjkslbmncy5hxi</a> </span>
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