Abstract
The two most common aging-related diseases, Alzheimer’s disease and type 2 diabetes mellitus, are associated with accumulation of amyloid proteins (β-amyloid and amylin, respectively). This amylin aggregation is reportedly cytotoxic to neurons. We found that aggregation of human amylin (hAmylin) induced neuronal apoptosis without obvious microglial infiltration in vivo. High concentrations of hAmylin irreversibly aggregated on the surface of the neuronal plasma membrane. Long-term incubation with hAmylin induced morphological changes in neurons. Moreover, hAmylin permeabilized the neuronal membrane within 1 min in a manner similar to Triton X-100, allowing impermeable fluorescent antibodies to enter the neurons and stain intracellular antigens. hAmylin also permeabilized the cell membrane of astrocytes, though more slowly. Under scanning electron microscopy, we observed that hAmylin destroyed the integrity of the cell membranes of both neurons and astrocytes. Additionally, it increased intracellular reactive oxygen species generation and reduced the mitochondrial membrane potential. Thus, by aggregating on the surface of neurons, hAmylin impaired the cell membrane integrity, induced reactive oxygen species production, reduced the mitochondrial membrane potential, and ultimately induced neuronal apoptosis.
Highlights
Alzheimer’s disease and type 2 diabetes mellitus (DM2) are the most common aging-related diseases [1, 2]
We previously found that a brief application of human amylin (hAmylin) could activate the transient receptor potential vanilloid 4 channels (TRPV4, the non-selective cation channels that are sensitive to mechanical stimulation and osmotic pressure [21,22,23]) and increase the [Ca2+]i in cultured hippocampal neurons [14]
Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was used to detect neuronal apoptosis induced by hAmylin
Summary
Alzheimer’s disease and type 2 diabetes mellitus (DM2) are the most common aging-related diseases [1, 2]. Multiple studies have indicated that there is a strong correlation between these two diseases, and about 80% of Alzheimer’s disease patients are estimated to have an impaired glucose tolerance or DM2 [3]. Protein aggregation has been linked to the pathogenesis of aging-related degenerative diseases [4]. Amylin aggregation causes pancreatic β-cell damage and insulin deficiency, which are components of the pathogenesis of DM2 [5]. Like β-amyloid, human amylin (hAmylin) tends to misfold into toxic structures and form amyloid deposits [6, 7] as protein degradation decreases with aging [4]
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