Abstract The progressive accumulation of amyloid-β and glutamate in synapses is a characteristic feature of early-stage Alzheimer’s disease. This study investigated the influence of transmembrane osmotic pressure on Alzheimer’s disease pathogenesis using a fluorescence resonance energy transfer–based optical probe for intermediate filament tension. Cotreatment with amyloid-β and glutamate at predicted cerebrospinal fluid levels induced Alzheimer’s disease–like neuronal injury. Probe-transfected cells were used to monitor intermediate filament tension, whereas cytoplasmic osmolality was measured using a freezing point osmometer under individual and combined treatment with amyloid-β and glutamate. The results showed that the combined treatment of 50 nM amyloid-β and 0.3 mM glutamate significantly elevated intermediate filament tension and osmotic pressure. Cellular experiments indicated that this increase resulted from the formation of intracellular protein nanoparticles through nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome formation and cytoskeletal depolymerization. Oligomers of 50 nm amyloid-β induced an outward membrane current, whereas 0.3 mM glutamate increased both amyloid-β-induced current and calcium signals. The increase in protein nanoparticle levels and Ca 2+ signals promoted voltage-dependent nonselective cation and anion influx, resulting in upregulated osmotic pressure, which was closely associated with the sensitization of ion channels elicited by calmodulin and protein kinase C activation. The attenuation of intracellular protein nanoparticles and desensitization of ion channels by drug combinations effectively alleviated transmembrane osmotic pressure and Alzheimer’s disease-like neuronal injury. Behavioral assays performed using Caenorhabditis elegans Alzheimer’s disease models further confirmed the efficacy of drug combinations. Therefore, protein nanoparticle-induced osmotic pressure plays a pivotal role in Alzheimer’s disease pathogenesis, particularly in response to amyloid-β and glutamate cotreatment. Restoring intracellular osmotic pressure seems to be a potential target for developing new effective therapeutic strategies for Alzheimer’s disease.
Ruan et al. (Thu,) studied this question.