Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2017

Open Access 01-12-2017 | Research article

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

Authors: Yue Wang, Zheng Wu, Yu-Ting Bai, Gang-Yi Wu, Gong Chen

Published in: Molecular Neurodegeneration | Issue 1/2017

Login to get access

Abstract

Background

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 the 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.
Appendix
Available only for authorised users
Literature
1.
Tanzi RE, Bertram L. Twenty years of the Alzheimer’s disease amyloid hypothesis: a genetic perspective. Cell. 2005;120:545–55.
2.
Jo S, Yarishkin O, Hwang YJ, Chun YE, Park M, Woo DH, Bae JY, Kim T, Lee J, Chun H, et al. GABA from reactive astrocytes impairs memory in mouse models of Alzheimer’s disease. Nat Med. 2014;20:886–96.
3.
Wu Z, Guo Z, Gearing M, Chen G. Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzheimer’s [corrected] disease model. Nat Commun. 2014;5:4159.PubMedPubMedCentral
4.
5.
Verret L, Mann EO, Hang GB, Barth AM, Cobos I, Ho K, Devidze N, Masliah E, Kreitzer AC, Mody I, et al. Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model. Cell. 2012;149:708–21.CrossRefPubMedPubMedCentral
6.
Schmid LC, Mittag M, Poll S, Steffen J, Wagner J, Geis HR, Schwarz I, Schmidt B, Schwarz MK, Remy S, Fuhrmann M. Dysfunction of Somatostatin-Positive Interneurons Associated with Memory Deficits in an Alzheimer’s Disease Model. Neuron. 2016;92:114–25.CrossRefPubMed
7.
Andrews-Zwilling Y, Bien-Ly N, Xu Q, Li G, Bernardo A, Yoon SY, Zwilling D, Yan TX, Chen L, Huang Y. Apolipoprotein E4 causes age- and Tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice. J Neurosci. 2010;30:13707–17.CrossRefPubMedPubMedCentral
8.
Albuquerque MS, Mahar I, Davoli MA, Chabot JG, Mechawar N, Quirion R, Krantic S. Regional and sub-regional differences in hippocampal GABAergic neuronal vulnerability in the TgCRND8 mouse model of Alzheimer’s disease. Front Aging Neurosci. 2015;7:30.CrossRefPubMedPubMedCentral
9.
Erlander MG, Tillakaratne NJ, Feldblum S, Patel N, Tobin AJ. Two genes encode distinct glutamate decarboxylases. Neuron. 1991;7:91–100.CrossRefPubMed
10.
11.
Chattopadhyaya B, Di Cristo G, Wu CZ, Knott G, Kuhlman S, Fu Y, Palmiter RD, Huang ZJ. GAD67-mediated GABA synthesis and signaling regulate inhibitory synaptic innervation in the visual cortex. Neuron. 2007;54:889–903.CrossRefPubMedPubMedCentral
12.
Sandhu KV, Lang D, Muller B, Nullmeier S, Yanagawa Y, Schwegler H, Stork O. Glutamic acid decarboxylase 67 haplodeficiency impairs social behavior in mice. Genes Brain Behav. 2014;13:439–50.CrossRefPubMed
13.
Kash SF, Johnson RS, Tecott LH, Noebels JL, Mayfield RD, Hanahan D, Baekkeskov S. Epilepsy in mice deficient in the 65-kDa isoform of glutamic acid decarboxylase. Proc Natl Acad Sci U S A. 1997;94:14060–5.CrossRefPubMedPubMedCentral
14.
Kimoto S, Bazmi HH, Lewis DA. Lower expression of glutamic acid decarboxylase 67 in the prefrontal cortex in schizophrenia: contribution of altered regulation by Zif268. Am J Psychiat. 2014;171:969–78.CrossRefPubMedPubMedCentral
15.
Benes FM, Lim B, Matzilevich D, Walsh JP, Subburaju S, Minns M. Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars. Proc Natl Acad Sci U S A. 2007;104:10164–9.CrossRefPubMedPubMedCentral
16.
Lanoue AC, Dumitriu A, Myers RH, Soghomonian JJ. Decreased glutamic acid decarboxylase mRNA expression in prefrontal cortex in Parkinson's disease. Exp Neurol. 2010;226:207–17.CrossRefPubMedPubMedCentral
17.
LeWitt PA, Rezai AR, Leehey MA, Ojemann SG, Flaherty AW, Eskandar EN, Kostyk SK, Thomas K, Sarkar A, Siddiqui MS, et al. AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial. Lancet Neurol. 2011;10:309–19.CrossRefPubMed
18.
Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft J, Van Eldik L, et al. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J Neurosci. 2006;26:10129–40.CrossRefPubMed
19.
Chen L, McKenna JT, Leonard MZ, Yanagawa Y, McCarley RW, Brown RE. GAD67-GFP knock-in mice have normal sleep-wake patterns and sleep homeostasis. Neuroreport. 2010;21:216–20.CrossRefPubMedPubMedCentral
20.
Tamamaki N, Yanagawa Y, Tomioka R, Miyazaki J, Obata K, Kaneko T. Green fluorescent protein expression and colocalization with calretinin, parvalbumin, and somatostatin in the GAD67-GFP knock-in mouse. J Comp Neurol. 2003;467:60–79.CrossRefPubMed
21.
Sadleir KR, Eimer WA, Cole SL, Vassar R. Abeta reduction in BACE1 heterozygous null 5XFAD mice is associated with transgenic APP level. Mol Neurodegener. 2015;10:1.CrossRefPubMedPubMedCentral
22.
Ting JT, Daigle TL, Chen Q, Feng G. Acute brain slice methods for adult and aging animals: application of targeted patch clamp analysis and optogenetics. Methods Mol Biol. 2014;1183:221–42.CrossRefPubMedPubMedCentral
23.
Wesson DW, Levy E, Nixon RA, Wilson DA. Olfactory dysfunction correlates with amyloid-beta burden in an Alzheimer’s disease mouse model. J Neurosci. 2010;30:505–14.CrossRefPubMedPubMedCentral
24.
Selkoe DJ. The therapeutics of Alzheimer’s disease: where we stand and where we are heading. Ann Neurol. 2013;74:328–36.CrossRefPubMed
25.
Eimer WA, Vassar R. Neuron loss in the 5XFAD mouse model of Alzheimer’s disease correlates with intraneuronal Abeta42 accumulation and Caspase-3 activation. Mol Neurodegener. 2013;8:2.CrossRefPubMedPubMedCentral
26.
Zhang Z, Song M, Liu X, Kang SS, Kwon IS, Duong DM, Seyfried NT, Hu WT, Liu Z, Wang JZ, et al. Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease. Nat Med. 2014;20:1254–62.CrossRefPubMedPubMedCentral
27.
Clarkson AN, Huang BS, Macisaac SE, Mody I, Carmichael ST. Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke. Nature. 2010;468:305–9.CrossRefPubMedPubMedCentral
28.
Lee M, Schwab C, McGeer PL. Astrocytes are GABAergic cells that modulate microglial activity. Glia. 2011;59:152–65.CrossRefPubMed
29.
Stamps JJ, Bartoshuk LM, Heilman KM. A brief olfactory test for Alzheimer’s disease. J Neurol Sci. 2013;333:19–24.CrossRefPubMed
30.
31.
Cramer PE, Cirrito JR, Wesson DW, Lee CY, Karlo JC, Zinn AE, Casali BT, Restivo JL, Goebel WD, James MJ, et al. ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science. 2012;335:1503–6.CrossRefPubMedPubMedCentral
32.
Palop JJ, Mucke L. Amyloid-beta-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat Neurosci. 2010;13:812–8.CrossRefPubMedPubMedCentral
33.
Asada H, Kawamura Y, Maruyama K, Kume H, Ding R, Ji FY, Kanbara N, Kuzume H, Sanbo M, Yagi T, Obata K. Mice lacking the 65 kDa isoform of glutamic acid decarboxylase (GAD65) maintain normal levels of GAD67 and GABA in their brains but are susceptible to seizures. Biochem Biophys Res Commun. 1996;229:891–5.CrossRefPubMed
34.
Asada H, Kawamura Y, Maruyama K, Kume H, Ding RG, Kanbara N, Kuzume H, Sanbo M, Yagi T, Obata K. Cleft palate and decreased brain gamma-aminobutyric acid in mice lacking the 67-kDa isoform of glutamic acid decarboxylase. Proc Natl Acad Sci U S A. 1997;94:6496–9.CrossRefPubMedPubMedCentral
35.
Li Y, Sun H, Chen Z, Xu H, Bu G, Zheng H. Implications of GABAergic Neurotransmission in Alzheimer’s Disease. Front Aging Neurosci. 2016;8:31.PubMedPubMedCentral
36.
37.
Mitew S, Kirkcaldie MT, Dickson TC, Vickers JC. Altered synapses and gliotransmission in Alzheimer’s disease and AD model mice. Neurobiol Aging. 2013;34:2341–51.CrossRefPubMed
38.
Lee M, McGeer EG, McGeer PL. Mechanisms of GABA release from human astrocytes. Glia. 2011;59:1600–11.CrossRefPubMed
39.
Horvath L, van Marion I, Tai K, Nielsen TT, Lundberg C. Knockdown of GAD67 protein levels normalizes neuronal activity in a rat model of Parkinson's disease. J Gene Med. 2011;13:188–97.CrossRefPubMed
40.
Bero AW, Yan P, Roh JH, Cirrito JR, Stewart FR, Raichle ME, Lee JM, Holtzman DM. Neuronal activity regulates the regional vulnerability to amyloid-beta deposition. Nat Neurosci. 2011;14:750–6.CrossRefPubMedPubMedCentral
41.
Wu J, Petralia RS, Kurushima H, Patel H, Jung MY, Volk L, Chowdhury S, Shepherd JD, Dehoff M, Li Y, et al. Arc/Arg3.1 regulates an endosomal pathway essential for activity-dependent beta-amyloid generation. Cell. 2011;147:615–28.CrossRefPubMedPubMedCentral
42.
Iaccarino HF, Singer AC, Martorell AJ, Rudenko A, Gao F, Gillingham TZ, Mathys H, Seo J, Kritskiy O, Abdurrob F, et al. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature. 2016;540:230–5.CrossRefPubMed
43.
Sun Y, Wu Z, Kong S, Jiang D, Pitre A, Wang Y, Chen G. Regulation of epileptiform activity by two distinct subtypes of extrasynaptic GABAA receptors. Mol Brain. 2013;6:21.CrossRefPubMedPubMedCentral
44.
Mann EO, Mody I. Control of hippocampal gamma oscillation frequency by tonic inhibition and excitation of interneurons. Nat Neurosci. 2010;13:205–12.CrossRefPubMed
45.
Ferando I, Mody I. In vitro gamma oscillations following partial and complete ablation of delta subunit-containing GABAA receptors from parvalbumin interneurons. Neuropharmacology. 2015;88:91–8.CrossRefPubMed
46.
Allaman I, Belanger M, Magistretti PJ. Astrocyte-neuron metabolic relationships: for better and for worse. Trends Neurosci. 2011;34:76–87.CrossRefPubMed
47.
Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, et al. Inflammation and Alzheimer’s disease. Neurobiol Aging. 2000;21:383–421.CrossRefPubMedPubMedCentral
48.
49.
Heppner FL, Ransohoff RM, Becher B. Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci. 2015;16:358–72.CrossRefPubMed
50.
Carmans S, Hendriks JJ, Slaets H, Thewissen K, Stinissen P, Rigo JM, Hellings N. Systemic treatment with the inhibitory neurotransmitter gamma-aminobutyric acid aggravates experimental autoimmune encephalomyelitis by affecting proinflammatory immune responses. J Neuroimmunol. 2013;255:45–53.CrossRefPubMed
51.
Limon A, Reyes-Ruiz JM, Miledi R. GABAergic drugs and Alzheimer’s disease. Future Med Chem. 2011;3:149–53.CrossRefPubMed
Metadata
Title
Gad67 haploinsufficiency reduces amyloid pathology and rescues olfactory memory deficits in a mouse model of Alzheimer’s disease
Authors
Yue Wang
Zheng Wu
Yu-Ting Bai
Gang-Yi Wu
Gong Chen
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2017
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-017-0213-9

Other articles of this Issue 1/2017

Molecular Neurodegeneration 1/2017 Go to the issue

Methodology

Separation of photoreceptor cell compartments in mouse retina for protein analysis

Research article

APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice

Correction

Correction to: Gene-environment interaction between lead and Apolipoprotein E4 causes cognitive behavior deficits in mice

Research article

Ex vivo 18O-labeling mass spectrometry identifies a peripheral amyloid β clearance pathway

Research article

Humanized monoclonal antibody armanezumab specific to N-terminus of pathological tau: characterization and therapeutic potency

Research article

Intranasal insulin reverts central pathology and cognitive impairment in diabetic mother offspring