Brain Advance Access published online on August 4, 2008
Brain, doi:10.1093/brain/awn174
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Soluble amyloid-β peptides potently disrupt hippocampal synaptic plasticity in the absence of cerebrovascular dysfunction in vivo
1Trinity College Institute of Neuroscience, 2Department of Pharmacology and Therapeutics, Trinity College, Dublin 2 and 3Laboratory for Neurodegenerative Research, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland
Correspondence to:
Michael J. Rowan, Department of Pharmacology and Therapeutics, Biotechnology Building, Trinity College, Dublin 2, Ireland E-mail: mrowan{at}tcd.ie.
Long before the onset of clinical Alzheimer's disease non-fibrillar, soluble assembly states of amyloid-β (Aβ) peptides are believed to cause cognitive problems by disrupting synaptic function in the absence of significant neurodegeneration. Since many of the risk factors for Alzheimer's disease are vascular, impairment of cerebral blood flow by soluble Aβ has been proposed to be critical in triggering these early changes. However, it is not known if soluble Aβ can affect cerebrovascular function at the concentrations required to cause inhibition of synaptic plasticity mechanisms believed to underlie the early cognitive deficits of Alzheimer's disease. Here we developed a new method to simultaneously assess the ability of soluble Aβ to impair plasticity at synapses and to affect resting and activity-dependent local blood flow in the rat hippocampus in vivo. Intracerebroventricular injection of soluble synthetic Aβ40 dimers rapidly inhibited plasticity of excitatory synaptic transmission at doses (10–42 pmol) comparable to natural Aβ, but failed to affect vascular function measured using laser-Doppler flowmetry (LDF). Like wild-type Aβ40, the more vasculotropic Aβ produced by people with familial hemorrhagic stroke of the Dutch type (Aβ40E22Q), impaired hippocampal plasticity without causing a significant change in local blood flow. Furthermore, neither resting nor activation-evoked hippocampal perfusion was affected by soluble Aβ42, even at a concentration that markedly (25%) reduced baseline synaptic transmission. These findings demonstrate that the putative synaptotoxic soluble Aβ species of early Alzheimer's disease cause synaptic dysfunction in the absence of detectible changes in local blood flow. This strongly indicates that early cognitive deficits can be caused by soluble Aβ independently of deleterious effects on cerebrovascular dynamics.
Key Words: cerebral blood flow; functional hyperaemia; synaptic transmission; amyloid-β oligomers; Alzheimer's disease
Abbreviations:
Aβ, amyloid-β protein; AMPA, 
-amino-3-hydroxy-5-methylisoxazole-4-propionic acid; D-AP5, D-(-)-2-amino-5-phosphonopentanoic acid; EPSP, excitatory postsynaptic potential; HBF, hippocampal blood flow; HFS, high frequency stimulation; LDF, laser-Doppler flowmetry; LTP, long-term potentiation; NMDA, N-methyl-D-aspartate
Received May 1, 2008. Revised June 17, 2008. Accepted July 4, 2008.