Amyloid beta from axons and dendrites reduces local spine number and plasticity.
Excessive synaptic loss is thought to be one of the earliest events in Alzheimer's disease. Amyloid beta (Abeta), a peptide secreted in an activity-modulated manner by neurons, has been implicated in the pathogenesis of Alzheimer's disease by removing dendritic spines, sites of excitatory synaptic transmission. However, issues regarding the subcellular source of Abeta, as well as the mechanisms of its production and actions that lead to synaptic loss, remain poorly understood. In rat organotypic slices, we found that acute overproduction of either axonal or dendritic Abeta reduced spine density and plasticity at nearby ( approximately 5-10 mum) dendrites. The production of Abeta and its effects on spines were sensitive to blockade of action potentials or nicotinic receptors; the effects of Abeta (but not its production) were sensitive to NMDA receptor blockade. Notably, only 30-60 min blockade of Abeta overproduction permitted induction of plasticity. Our results indicate that continuous overproduction of Abeta at dendrites or axons acts locally to reduce the number and plasticity of synapses.
Wei
Wei
W
Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
Nguyen
Louis N
LN
Kessels
Helmut W
HW
Hagiwara
Hiroaki
H
Sisodia
Sangram
S
Malinow
Roberto
R
D000200:Action Potentials / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000502:physiology*; D003712:Dendrites / Q000378:metabolism / Q000502:physiology*; D049229:Dendritic Spines / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology; D066298:In Vitro Techniques; D009473:Neuronal Plasticity / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism; D017966:Pyramidal Cells / Q000378:metabolism / Q000502:physiology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism; D013569:Synapses / Q000502:physiology*; D013997:Time Factors
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; C075222:amyloid beta-protein (1-42)