Expression of beta-amyloid induced age-dependent presynaptic and axonal changes in Drosophila.
Alzheimer's disease (AD) is attributable to synapse dysfunction and loss, but the nature and progression of the presynaptic structural and functional changes in AD are essentially unknown. We expressed wild-type or arctic form of beta amyloid(1-42) (Abeta) in a small group of neurons in the adult fly and performed extensive time course analysis of the function and structure of both axon and presynaptic terminals at the identified single-neuron level. Abeta accumulated intracellularly and induced a range of age-dependent changes, including depletion of presynaptic mitochondria, slowdown of bi-directional transports of axonal mitochondria, decreased synaptic vesicles, increased large vacuoles, and elevated synaptic fatigue. These structural and functional synaptic changes correlated with age-dependent deficit in motor behavior. All these alterations were accelerated in flies expressing the arctic form of Abeta. The depletion of presynaptic mitochondria was the earliest detected phenotype and was not caused by the change in axonal transport of mitochondria. Moreover, axonal mitochondria exhibited a dramatic reduction in number but a significant increase in size in aged Abeta-expressing flies, indicating a global depletion of mitochondria in the neuron and an impairment of mitochondria fission. These results suggest that Abeta accumulation depletes presynaptic and axonal mitochondria, leading to other presynaptic deficits.
Zhao
Xiao-Liang
XL
Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Wang
Wen-An
WA
Tan
Jiang-Xiu
JX
Huang
Jian-Kang
JK
Zhang
Xiao
X
Zhang
Bao-Zhu
BZ
Wang
Yu-Hang
YH
YangCheng
Han-Yu
HY
Zhu
Hong-Lian
HL
Sun
Xiao-Jiang
XJ
Huang
Fu-De
FD
D000375:Aging / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001370:Axonal Transport / Q000235:genetics; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D004330:Drosophila / Q000378:metabolism* / Q000648:ultrastructure; D004734:Energy Metabolism / Q000235:genetics; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000502:physiology; D013572:Synaptic Vesicles / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D014617:Vacuoles / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D014855:Wallerian Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D016229:Amyloid beta-Peptides