Abstract
Alzheimer's disease is characterized by cognitive decline, neuronal degeneration, and the accumulation of amyloid-beta (Aβ). Although, the neurotoxic Aβ peptide is widely believed to trigger neuronal dysfunction and degeneration in Alzheimer's disease, the mechanism by which this occurs is poorly defined. Here we describe a novel, Aβ-triggered apoptotic pathway in which Aβ treatment leads to the upregulation of G-protein activated inwardly rectifying potassium (GIRK/Kir3) channels, causing potassium efflux from neurons and Aβ-mediated apoptosis. Although, GIRK channel activity is required for Aβ-induced neuronal degeneration, we show that it is not sufficient, with coincident signaling by the p75 neurotrophin receptor (p75NTR) also required for potassium efflux and cell death. Our results identify a novel role for GIRK channels in mediating apoptosis, and provide a previously missing mechanistic link between the excitotoxicity of Aβ and its ability to trigger cell death pathways, such as that mediated by p75NTR. We propose that this death-signaling pathway contributes to the dysfunction of neurons in Alzheimer's disease and is responsible for their eventual degeneration.
Highlights
Alzheimer’s disease is a progressive neurodegenerative disorder that is characterized by deficits in memory and higher cognitive function
We have demonstrated that exposure to excitotoxic amyloid β (Aβ) drives an increase in the number of surface GIRK channels which, when activated, can directly result in increased inhibitory neurotransmission and neuronal circuit silencing
GIRK channel activity is a key mediator of neuronal degeneration and apoptosis
Summary
Alzheimer’s disease is a progressive neurodegenerative disorder that is characterized by deficits in memory and higher cognitive function. The 42 amino acid form of Aβ (Aβ42) readily aggregates into soluble oligomers (Haass and Selkoe, 2007) which can directly contribute to neuronal and synaptic dysfunction and degeneration (Walsh et al, 2002; Haass and Selkoe, 2007; Walsh and Selkoe, 2007; Shankar et al, 2008) These Aβ-mediated changes, which include the loss of dendritic spines and neurites (Mucke et al, 2000; Smith et al, 2009; Perez-Cruz et al, 2011), GIRK Channels Mediate Amyloid β Toxicity have been proposed to cause the cognitive decline, which precedes neuronal death in Alzheimer’s disease (Ondrejcak et al, 2010; Palop and Mucke, 2010). An alternative mechanism of Aβ-induced neurodegeneration is via the p75 neurotrophin receptor (p75NTR). p75NTR initiates apoptosis in a variety of neurodegenerative conditions, including apoptotic death triggered by oligomeric forms of Aβ42 in vitro (Yang et al, 2008; Coulson et al, 2009) and in animal models of Alzheimer’s disease (Sotthibundhu et al, 2008; Knowles et al, 2009; Wang et al, 2011). p75NTR is expressed throughout life in basal forebrain cholinergic neurons and is ectopically upregulated in response to Aβ accumulation in other diseasevulnerable brain areas, such as the cortex and hippocampus (Mufson and Kordower, 1992; Chakravarthy et al, 2010; Perez et al, 2011), and in other excitotoxic disease conditions such as motor neuron disease and epilepsy (Ibanez and Simi, 2012)
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