A Study Of Mechanisms Underlying β-amyloid Induced Acute Impairment Of Hippocampal Neurons

Insoluble fibril deposits ofβamyloid (Aβ) forms extracellular senile plaques, which is the major pathological hallmarks in Alzheimer's disease (AD). Aβis believed to be the culprit behind neurodegeneration and associated cognitive and behavioral abnormalities. Although there is ample evidence that Aβfibrils exert a variety of toxicity to neurons and recent studies indicate that intermediate Aβaggregates can profoundly inhibit synaptic functions, the cellular mechanisms underlying Aβinhibition on synaptic and other neuronal functions, however, remain elusive. Hence, we investigated the acute effect of Aβon primary cultured hippocampal neurons and the underlying mechanisms. We obtained the following results:First, different toxic fragments of Aβeffect on [Ca²⁺]_i differentially. Aβ_25-35 significantly inhibited the synchronized spontaneous cytoplasmic Ca²⁺ transients immediately after application, whereas it had little effect on the baseline of [Ca²⁺]_i in neurons. Aβ_1-42 had similar effect on the Ca²⁺ transients as Aβ_25-35, while it elevated the baseline of [Ca²⁺]_i gradually. However Aβ_1-40 had little effect on either Ca²⁺ transients or baseline of [Ca²⁺]_i.Secondly, a brief exposure of cultured hippocampal neurons to Aβmolecules resulted in rapid and severe impairment of mitochondrial transport without inducing apparent cell death and significant morphological changes. Such acute inhibition of mitochondrial transport was not associated with a disruption of mitochondria potential and nor involved aberrant cytoskeletal changes. Aβalso did not elicit significant Ca²⁺ signaling to affect transport. Thirdly, protein kinase A (PKA) inhibition had no effects onmitochondrial transport and Aβimpairment, while stimulation of PKA or inhibition of glycogen synthase kinase 3β(GSK3β) effectively attenuated the acute inhibition of mitochondrial transport by Aβ. These data indicate an important role for GSK3βin the acute actions of Aβon transport and suggest that PKA may alleviate Aβinhibition by modulating GSK3βactivity.Finally, we found that exposure of hippocampal neurons to Aβonly induced marked cell death after 6 hr. This suggests that the acute impairment of [Ca²⁺]_i signal and mitochondrial transport are unlikely to be a consequence of Aβinduced cell death.