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The Journal of Neuroscience, October 11, 2006, 26(41):10480-10487; doi:10.1523/JNEUROSCI.3231-06.2006

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Development/Plasticity/Repair
Acute Impairment of Mitochondrial Trafficking by -Amyloid Peptides in Hippocampal Neurons

Yanfang Rui,^1 * Priyanka Tiwari,^2 * Zuoping Xie,¹ and James Q. Zheng²

¹Department of Biological Science and Biotechnology, State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua University, Beijing, China 100084, and ²Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854

Correspondence should be addressed to either of the following: Dr. James Q. Zheng, Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854, Email: james.zheng{at}umdnj.edu; or Zuoping Xie, Department of Biological Science and Biotechnology, Tsinghua University, Beijing, China 100084, Email: zuopingx{at}tsinghua.edu.cn

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

Key words: Apeptide; Alzheimer's disease; signal transduction; actin; calcium; cAMP; transport

---

Received March 23, 2006; accepted Aug. 27, 2006.

Correspondence should be addressed to either of the following: Dr. James Q. Zheng, Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854, Email: james.zheng{at}umdnj.edu; or Zuoping Xie, Department of Biological Science and Biotechnology, Tsinghua University, Beijing, China 100084, Email: zuopingx{at}tsinghua.edu.cn

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