IS ALZHEIMER'S AMYLOID PLAQUE FORMATION A CONDITION FOR NEURONAL DYSFUNCTION ?

A.R. Koudinov^1,2; N.V. Koudinova^1,2; T.T. Berezov¹

1. Russian Acad Med Sci, Nat Mental Health Res Ctr, Inst Biomed Chem, Timoshenko 38-27, Moscow 121359, Russian Federation

2. Neurobiol and Biol Regulation, Weizmann Institute, Rehovot 76100, Israel

Diffuse amyloid deposits, 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. 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 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) long term potentiation (LTP) were expressed as a fEPSP slope change versus stimulus intensity and time. Immunohistochemistry of slices with 4G8 and 6E10 antibodies revealed extracellular hippocampal immunoreactivity of mouse Abeta in both TG and WT and confirmed deposits of human Abeta in the TG hippocampus. We also performed congo red staining of slices and found amyloid birefringence 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 a senile plaque formation, and ii) confirm 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) may contribute to the neuronal dysfunction.