Amyloid-β-Associated Alterations in Excitatory/Inhibitory Balance in Caenorhabditis elegans

Alzheimer’s disease (AD) is characterized by abnormal amyloid-β (Aβ) aggregation and neuronal loss. Disruption of the balance between excitatory and inhibitory (E/I) neurotransmission may contribute to disease progression. Here, we investigated E/I imbalance in transgenic C. elegans AD models expressing neuronal Aβ. The neuromuscular junction provides a well-characterized system for assessing E/I balance. In young animals (YA), Aβ expression did not alter E/I balance. However, aged animals exhibited increased cholinergic sensitivity (24% and 84% of AD models paralyzed vs 6% and 65% in wild-type (WT), after 30 and 90 min of levamisole exposure, respectively). These findings suggest age-dependent impairment of E/I signaling. Consistently, GABA-dependent escape-response assays revealed functional deficits in aged AD animals (51 ± 6% vs 69 ± 17% in WT). To determine whether Aβ promotes neurodegeneration before functional decline, we assessed GABAergic neuron morphology. Interestingly, despite absence of detectable E/I alterations, 55% of YA AD model animals already exhibited morphological defects, including truncated or misguided neuronal processes. Overall, this study contributes to understanding how Aβ-associated structural damage and E/I signaling alterations emerge during aging, highlighting the progressive dysfunction in AD pathophysiology.