Amyloid beta impairs mitochondrial anterograde transport and degenerates synapses in Alzheimer's disease neurons

Loss of synapses and synaptic damage are the best correlates of cognitive decline identified in patients with Alzheimer's disease (AD), and mitochondrial oxidative damage and synaptic pathology have been identified as early events in the progression of AD. The progressive accumulation of amyloid beta (A beta) in synapses and synaptic mitochondria are hypothesized to cause synaptic degeneration and cognitive decline in patients with AD. However, the precise mechanistic link between A beta and mitochondria is not well understood. The purpose of this study was to better understand the effects of A beta on mitochondrial axonal transport and synaptic alterations in AD. Using mouse hippocampal neurons and A beta(25-35) peptide, we studied axonal transport of mitochondria, including mitochondrial motility, mitochondrial length and size, mitochondrial index per neurite, and synaptic alterations of the hippocampal neurons. In the PBS-treated neurons, 36.4 +/- 4.7% of the observed mitochondria were motile, with 21.0 +/- 1.3% moving anterograde and 15.4 +/- 3.4% moving retrograde and the average speed of movement was 12.1 +/- 1.8 mu m/min. In contrast, in the A beta-treated neurons, the number of motile mitochondria were significantly less, at 20.4 +/- 2.6% (P<0.032), as were those moving anterograde (10.1 +/- 2.6%, P<0.016) relative to PBS-treated neurons, suggesting that the A beta(25-35) peptide impairs axonal transport of mitochondria in AD neurons. In the All-treated neurons, the average speed of motile mitochondria was also less, at 10.9 +/- 1.9 mu m/min, and mitochondrial length was significantly decreased. Further, synaptic immunoreactivity was also significantly less in the A beta-treated neurons relative to the PBS-treated neurons, indicating that A beta affects synaptic viability. These findings suggest that, in neurons affected by AD, A beta is toxic, impairs mitochondrial movements, reduces mitochondrial length, and causes synaptic degeneration. (C) 2011 Elsevier B.V. All rights reserved.