Acute impairment of mitochondrial trafficking by β-amyloid peptides in hippocampal neurons

Defects in axonal transport are often associated with a wide variety of neurological diseases including Alzheimer's disease (AD). beta-Amyloid (A beta) 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 A beta 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. A beta 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 A beta inhibited mitochondrial transport by acting through glycogen synthase kinase 3 beta (GSK3 beta). Given that mitochondria are crucial organelles for many cellular functions and survival, our findings thus identify an important acute action of A beta molecules on nerve cells that could potentially contribute to various abnormalities of neuronal functions under AD conditions. Manipulation of GSK3 beta and PKA activities may represent a key approach for preventing and alleviating A beta cytotoxicity and AD pathological conditions.