Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Aug;16(8):1550-1551.
doi: 10.4103/1673-5374.300987.

Therapeutic potential of alpha 5 subunit containing GABAA receptors in Alzheimer's disease

Andrea Kwakowsky  1 , Henry J Waldvogel  1 , Richard L M Faull  1
Affiliations

Therapeutic potential of alpha 5 subunit containing GABAA receptors in Alzheimer's disease

Andrea Kwakowsky et al. Neural Regen Res. 2021 Aug.
No abstract available

PubMed Disclaimer

Conflict of interest statement

None

Figures

Figure 1
Figure 1
α5IA restores Aβ1–42-induced increase in ambient GABA levels, upregulation of α5GABAAR expression, and increase in tonic inhibitory conductance. The extra-synaptic high affinity α5GABAARs can be persistently activated by low concentrations of ambient GABA to generate tonic inhibition, which is important for learning and memory. Aβ1–42-induced increase in ambient GABA and upregulation of α5GABAAR expression could result in increased activation of α5GABAARs, leading to increased tonic inhibition, ultimately disrupting the excitatory/inhibitory balance, leading to network dysfunction and causing cell death which potentially contribute to the observed cognitive decline in Alzheimer’s disease. α5GABAARs are potential drug targets for the treatment of the disease. The inverse agonist α5IA acting through these receptors decreases Aβ1–42-induced increase in tonic inhibition, restores ambient GABA levels, and expression of α5GABAARs. Aβ: Amyloid-β; APP: amyloid precursor protein; α5IA: 3-(5-methylisoxazol-3-yl)-6-[(1-methyl-1,2,3-triazol-4-yl)methyloxy]-1,2,4-triazolo,3,4–a]phthalazine; GABA: gamma-aminobutyric acid; GABAAR: GABA type A receptor; GAD: glut amic acid decarboxylase; Glu: glutamate.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Atack JR. Preclinical and clinical pharmacology of the GABAA receptor alpha5 subtype-selective inverse agonist alpha5IA. Pharmacol Ther. 2010;125:11–26. - PubMed
    1. Busche MA, Chen X, Henning HA, Reichwald J, Staufenbiel M, Sakmann B, Konnerth A. Critical role of soluble amyloid-beta for early hippocampal hyperactivity in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A. 2012;109:8740–8745. - PMC - PubMed
    1. Calvo-Flores Guzman B, Kim S, Chawdhary B, Peppercorn K, Tate WP, Waldvogel HJ, Faull RL, Montgomery J, Kwakowsky A. Amyloid-beta1-42 -induced increase in GABAergic tonic conductance in mouse hippocampal CA1 pyramidal cells. Molecules. 2020 doi: 103390/molecules25030693. - PMC - PubMed
    1. Calvo-Flores Guzman B, Vinnakota C, Govindpani K, Waldvogel HJ, Faull RLM, Kwakowsky A. The GABAergic system as a therapeutic target for Alzheimer’s disease. J Neurochem. 2018;146:649–669. - PubMed
    1. Dawson GR, Maubach KA, Collinson N, Cobain M, Everitt BJ, MacLeod AM, Choudhury HI, McDonald LM, Pillai G, Rycroft W, Smith AJ, Sternfeld F, Tattersall FD, Wafford KA, Reynolds DS, Seabrook GR, Atack JR. An inverse agonist selective for alpha5 subunit-containing GABAA receptors enhances cognition. J Pharmacol Exp Ther. 2006;316:1335–1345. - PubMed