Small Aβ_1–42 oligomer‐induced membrane depolarization of neuronal and microglial cells: Role of N‐methyl‐D‐aspartate receptors

Abstract

Although it is well documented that soluble beta amyloid (Aβ) oligomers are critical factors in the pathogenesis of Alzheimer's disease (AD) by causing synaptic dysfunction and neuronal death, the primary mechanisms by which Aβ oligomers trigger neurodegeneration are not entirely understood. We sought to investigate whether toxic small Aβ(1-42) oligomers induce changes in plasma membrane potential of cultured neurons and glial cells in rat cerebellar granule cell cultures leading to neuronal death and whether these effects are sensitive to the N-methyl-D-aspartate receptor (NMDA-R) antagonist MK801. We found that small Aβ(1-42) oligomers induced rapid, protracted membrane depolarization of both neurons and microglia, whereas there was no change in membrane potential of astrocytes. MK801 did not modulate Aβ-induced neuronal depolarization. In contrast, Aβ1(-42) oligomer-induced decrease in plasma membrane potential of microglia was prevented by MK801. Small Aβ(1-42) oligomers significantly elevated extracellular glutamate and caused neuronal necrosis, and both were prevented by MK801. Also, small Aβ(1-42) oligomers decreased resistance of isolated brain mitochondria to calcium-induced opening of mitochondrial permeability transition pore. In conclusion, the results suggest that the primary effect of toxic small Aβ oligomers on neurons is rapid, NMDA-R-independent plasma membrane depolarization, which leads to neuronal death. Aβ oligomers-induced depolarization of microglial cells is NMDA-R dependent.

Detection of Amyloid Beta (Aβ) Oligomeric Composition Using Matrix-Assisted Laser Desorption Ionization Mass Spectrometry (MALDI MS)

“…to 55% upon exposure to Aβ oligomers while another reported 20% cellular viability after 48 hours [64][65].…”

An integrative genome-wide transcriptome reveals that candesartan is neuroprotective and a candidate therapeutic for Alzheimer’s disease

“…We used primary cultures of rat primary CGCs, which are very sensitive to glutamate excitotoxicity and extensively used in Alzheimer’s disease research [ 44 – 46 ]. CGCs were isolated from 8-day old Sprague Dawley rat pups (Charles Rivers Laboratories, Wilmington, MA, USA) as described previously [ 49 , 50 ] which were euthanized by decapitation.…”

“…This is a well-characterized and reliable primary neuronal model to analyze mechanisms and excitotoxic neuronal damage and neuroprotection [ 42 , 43 ]. Although in humans CGCs are not primary targets for Alzheimer’s disease, rat CGCs are very sensitive to glutamate excitotoxicity, a major early injury factor in this illness, and are extensively used in Alzheimer’s disease research [ 44 – 46 ]. We selected the ARB candesartan for our study because of its demonstrated neuroprotective effects on cultured primary cortical neurons, microglia and cerebrovascular endothelial cells, and its amelioration of brain inflammation in vivo [ 27 ] including reducing glutamate-induced apoptosis in cultured CGCs [ 25 ].…”

Aβ42 and Aβ40: similarities and differences

“…Only upon its aggregation it can induce the toxic effects. The aggregates of Aβ, especially oligomers, can induce increased oxidative stress [46], membrane permeability [47], change of cell skeleton, activation of apoptosis pathways in neural cells [48], and memory retention impairment [49]. However, the Aβ fibrils showed much lower toxicity compared with Aβ oligomer [50].…”