The new KV3.4 inhibitor BDS-I[1-8] as a potential pharmacological opportunity in Alzheimer's disease therapy

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and the first cause of dementia in the elderly, with no treatment able to prevent or to block disease progression. AD is characterized by memory impairment and cognitive dysfunction, followed in the late phases of the disease by severe neurodegeneration and neuronal death. The amyloid-β (Aβ) peptide, generated upon the processing of the amyloid precursor protein, is considered the main initiator of AD pathology. Indeed, Aβ peptides, which aggregate and accumulate to form extracellular plaques and intraneuronal deposits, trigger a sequence of pathogenic mechanisms including synaptic dysfunction, neuroinflammation and cell death, leading to cognitive alterations and, subsequently, to dementia. Aβ toxicity also consists in the dysregulation of ionic homeostasis, which contributes to neuronal dysfunction and death. Several studies reported an imbalance of potassium ion (K+) concentrations in AD brains and the alteration of K+ channel activity during AD (Etcheberrigaray and Bhagavan, 1999). K+ channels constitute a large family of ion channels that are involved in determining the resting membrane potential and the action potential waveform and duration and in regulating neurotransmitter release (Rudy et al., 1999). On the other hand, K+ channels are also implicated in the regulation of cell survival and apoptosis, since cytoplasmic K+ loss due to the overexpression of K+ channels has been shown to favor the activation of caspases and nucleases (Yu, 2003), which in turn contribute to the outcome of apoptosis