Acute Impairment of Mitochondrial Trafficking by β-Amyloid Peptides in Hippocampal Neurons

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Abstract
Defects in axonal transport are often associated with a wide variety of neurological diseases including Alzheimer's disease (AD). β-Amyloid (Aβ) is a major component of neuritic plaques associated with pathological conditions of AD brains. Here, we report that a brief exposure of cultured hippocampal neurons to Aβ molecules 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 nor involved aberrant cytoskeletal changes. Aβ also did not elicit significant Ca2+signaling to affect mitochondrial trafficking. However, stimulation of protein kinase A (PKA) by forskolin, cAMP analogs, or neuropeptides effectively alleviated the impairment. We also show that Aβ inhibited mitochondrial transport by acting through glycogen synthase kinase 3β (GSK3β). Given that mitochondria are crucial organelles for many cellular functions and survival, our findings thus identify an important acute action of Aβ molecules on nerve cells that could potentially contribute to various abnormalities of neuronal functions under AD conditions. Manipulation of GSK3β and PKA activities may represent a key approach for preventing and alleviating Aβ cytotoxicity and AD pathological conditions.