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

Abstract

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.

EEG/ERP evidence of possible hyperexcitability in older adults with elevated beta-amyloid

“…Such hyperactivity shifts the normal excitation/inhibition balance towards neuronal hyperexcitability, mediated through both increased excitation of synaptic glutamatergic tone and decreased GABAergic inhibition [ 4 ]. This relative neuronal hyperexcitability in turn leads to excitotoxicity [ 5 ] and amplification of synaptic release of Aβ [ 6 ], ultimately leading to further neurodegeneration and neuronal silencing mediated by concomitant tau accumulation [ 7 ]. Previous studies have explained this hyperexcitability as a physiological compensation for the increased Aβ burden in preclinical AD [ 8 – 11 ], wherein the accumulation of Aβ deposits results in neural recruitment, up until a certain threshold when the compensatory mechanisms fail.…”

Optogenetic Activation of Astrocytes—Effects on Neuronal Network Function

“…Shift in excitation and inhibition balance in neuronal network is often considered one of the causes of AD pathology [24,25]. It has been proposed that regulation of neuronal network activity in AD by stimulation of astrocytes may lead to beneficial effects by stabilizing activity of the network [26].…”

Hyperexcitability in Older Adults with Elevated Beta-Amyloid

“…(4) This relative neuronal hyperexcitability in turn leads to excitotoxicity,(5) amplification of synaptic release of Aβ, (6) and ultimately to further neurodegeneration and neuronal silencing mediated by concomitant tau accumulation. (7) Previous studies have explained this hyperexcitability as a physiological compensation for the increased Aβ burden in preclinical AD, (8)(9)(10)(11) wherein the accumulation of Aβ deposits results in neural recruitment, up until a certain threshold when the compensatory mechanisms fail. The hyperexcitability is then followed by hypoexcitability due to functional neuronal silencing in clinically diagnosed AD.…”

“…The hyperexcitability is then followed by hypoexcitability due to functional neuronal silencing in clinically diagnosed AD. (7) Electro-encephalography (EEG) offers insights into postsynaptic activity of pyramidal cells and may therefore be useful for evaluating the impact of Aβ deposits on neuronal excitability in the preclinical and clinical stages of AD in humans. (12) The results of a systematic review show consistent evidence of hypoexcitability, expressed as reduced power in the high frequency bands in AD, and lower amplitude and larger latency of event-related potentials (ERP).…”

“…The P3 component time window was established between 250 ms and 650 ms for all three tests. Average event-related power was identified for four frequency bands: delta [2-4 Hz], theta[4][5][6][7][8], alpha[8][9][10][11][12] and beta[12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] (30). Because of the prefrontal cortex involvement in working memory, we identified a priori Fz as the main channel, but also report the P3 ERP of channel locations Cz and Pz.…”