Next Article in Journal
Rational Computational Design of Fourth-Generation EGFR Inhibitors to Combat Drug-Resistant Non-Small Cell Lung Cancer
Next Article in Special Issue
Therapeutic Targeting Strategies for Early- to Late-Staged Alzheimer’s Disease
Previous Article in Journal
Adaptive Immune Responses in Human Atherosclerosis
Previous Article in Special Issue
Clinical Utility of the Pathogenesis-Related Proteins in Alzheimer’s Disease
Review

Modulation of Brain Hyperexcitability: Potential New Therapeutic Approaches in Alzheimer’s Disease

by 1,2,*, 3 and 1,2
1
Cognitive Neurology Group, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK
2
Wellcome Trust Centre for Integrative Neuroimaging, Department of Experimental Psychology, University of Oxford, Oxford OX2 6AE, UK
3
Oxford Epilepsy Research Group, Nuffield Department Clinical Neurosciences, John Radcliffe Hospital, Oxford OX3 9DU, UK
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(23), 9318; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239318
Received: 29 October 2020 / Revised: 30 November 2020 / Accepted: 5 December 2020 / Published: 7 December 2020
People with Alzheimer’s disease (AD) have significantly higher rates of subclinical and overt epileptiform activity. In animal models, oligomeric Aβ amyloid is able to induce neuronal hyperexcitability even in the early phases of the disease. Such aberrant activity subsequently leads to downstream accumulation of toxic proteins, and ultimately to further neurodegeneration and neuronal silencing mediated by concomitant tau accumulation. Several neurotransmitters participate in the initial hyperexcitable state, with increased synaptic glutamatergic tone and decreased GABAergic inhibition. These changes appear to activate excitotoxic pathways and, ultimately, cause reduced long-term potentiation, increased long-term depression, and increased GABAergic inhibitory remodelling at the network level. Brain hyperexcitability has therefore been identified as a potential target for therapeutic interventions aimed at enhancing cognition, and, possibly, disease modification in the longer term. Clinical trials are ongoing to evaluate the potential efficacy in targeting hyperexcitability in AD, with levetiracetam showing some encouraging effects. Newer compounds and techniques, such as gene editing via viral vectors or brain stimulation, also show promise. Diagnostic challenges include identifying best biomarkers for measuring sub-clinical epileptiform discharges. Determining the timing of any intervention is critical and future trials will need to carefully stratify participants with respect to the phase of disease pathology. View Full-Text
Keywords: Alzheimer’s disease; epilepsy; hyperexcitability; neurodegeneration Alzheimer’s disease; epilepsy; hyperexcitability; neurodegeneration
Show Figures

Figure 1

MDPI and ACS Style

Toniolo, S.; Sen, A.; Husain, M. Modulation of Brain Hyperexcitability: Potential New Therapeutic Approaches in Alzheimer’s Disease. Int. J. Mol. Sci. 2020, 21, 9318. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239318

AMA Style

Toniolo S, Sen A, Husain M. Modulation of Brain Hyperexcitability: Potential New Therapeutic Approaches in Alzheimer’s Disease. International Journal of Molecular Sciences. 2020; 21(23):9318. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239318

Chicago/Turabian Style

Toniolo, Sofia, Arjune Sen, and Masud Husain. 2020. "Modulation of Brain Hyperexcitability: Potential New Therapeutic Approaches in Alzheimer’s Disease" International Journal of Molecular Sciences 21, no. 23: 9318. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239318

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop