Age-related impairment of synaptic transmission but normal long-term potentiation in transgenic mice that overexpress the human APP695SWE mutant formof amyloid precursor protein

We have studied synaptic function in a transgenic mouse strain relevant to Alzheimer's disease (AD), overexpressing the 695 amino acid isoform of huma n amyloid precursor protein with K670N and M671L mutations (APP(695)SWE mic e), which is associated with early-onset familial AD. Aged-transgenic mice had substantially elevated levels of A beta (up to 22 mu mol/gm) and displa yed characteristic A beta plaques. Hippocampal slices from 12-month-old APP (695)SWE transgenic animals displayed reduced levels of synaptic transmissi on in the CA1 region when compared with wild-type littermate controls. Incl usion of the ionotropic glutamate receptor antagonist kynurenate during pre paration of brain slices abolished this deficit. At 18 months of age, a sel ective deficit in basal synaptic transmission was observed in the CA1 regio n despite treatment with kynurenate. Paired-pulse facilitation and long-ter m potentiation (LTP) were normal in APP(695)SWE transgenic mice at both 12 and 18 months of age. Thus, although aged APP(695)SWE transgenic mice have greatly elevated levels of A beta protein, increased numbers of plaques, an d reduced basal synaptic transmission, LTP can still be induced and express ed normally. We conclude that increased susceptibility to excitotoxicity ra ther than a specific effect on LTP is the primary cause of cognitive defici ts in APP(695)SWE mice.