ALZHEIMER'S AMYLOID PLAQUE FORMATION IS A CONDITION FOR NEURONAL DYSFUNCTION
A.R. Koudinov1,2 , T.T. Berezov1
1. Russian Academy of Medical Sciences, National Mental Health Research Center, Institute of Biomedical Chemistry, Timoshenko 38-27, Moscow 121359, Russian Federation
2. Weizmann Institute of Science, Department of Neurobiology and
Biological Regulation, Rehovot 76100, Israel
Diffuse amyloid deposits, amyloid plaques and vascular amyloid of Alzheimer’s and Down syndrome patients are considered to be an essential features of these pathologies. Nevertheless, there is no direct evidence that human brain amyloid, composing largely of amyloid beta protein (Abeta), has direct effect on neuronal dysfunction. An attempt to unravel this important issue was made in a recent report (Nature Neurosci.1999, 2: 271) on transgenic mice (TG) expressing human amyloid precursor protein (APP695) bearing swedish mutation. These TG developed “dramatically elevated concentrations of Abeta and significant Abeta deposits,” and had impaired spatial learning and hippocampal long term potentiation (LTP) (a long-lasting increase in synaptic transmission efficacy, LTP), the cellular model for neuronal plasticity, learning and memory. However, this report (as well as another earlier work (Nature 1997, 387: 500) on LTP deficit in TG expressing the carboxy-terminal 104 amino acids of APP) did not “determine whether the effects measured resulted from elevated concentrations of soluble Abeta, deposited Abeta or both”, and it is still unclear whether the maturation of brain amyloid deposits, particularly the development of congo red positive amyloid plaques, is an essential event leading to neuronal dysfunction.
In our study we further attempted to differentiate separate action of diffuse amyloid deposits and plaque amyloid on hippocampal synaptic plasticity in the model of 25.5 months old TG, expressing wild type human APP695, and corresponding wild type non-transgenic control (WT) mouse hippocampal slices using extracellular recording of CA1 field excitatory postsynaptic potentials (fEPSPs). The input/output (I/O) relationship, a basic parameter of synaptic physiology, and tetanus induced (t) LTP were expressed as a fEPSP slope change versus stimulus intensity and time, respectively, and the analysis was performed essentially as we described previously (J Neurosci.1999, 19: 9412). Immunohistochemistry of slices (40 micron sections prepared on a microtome from 400 micron slices (from the same preparations used for extracellular recording) and overnight fixed in 4% PFH) with 4G8 and 6E10 antibodies (Senetek, PLC., anti-human/mouse-Abeta17-24 and anti-human-Abeta1-17, respectively) revealed extracellular hippocampal immunoreactivity of mouse Abeta in both TG and WT and confirmed extracellular deposits of human Abeta in the TG hippocampus. We also performed congo red staining of slices and found amyloid fluorescence specifically in the TG, suggesting that expression of wild type human Abeta in mice lead to a mature plaque-like amyloid. Electrophysiological analysis revealed that TG (as compared to controls) expressed severe deficit in the tLTP and had lower I/O responses for the same high stimulation intensity.
Our data i) provide evidence that one of the causes of
synaptic plasticity deficit and neuronal dysfunction is an Alzheimer’s
mature senile plaque formation, and ii) suggest amyloidosis prevention
as an important therapeutic approach in AD. Our results also iii)
imply that in Down syndrome, characterized by diffuse amyloid deposition
in early life, the other factors (like oxidative stress condition or lipid
homeostasis misregulation) may contribute to the neuronal dysfunction.
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