Soluble oligomers of beta amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus.
The dementia in Alzheimer disease (AD) is usually attributed to widespread neuronal loss in conjunction with the pathologic hallmarks of intracellular neurofibrillary tangles and extracellular plaques containing amyloid (A beta) in fibrillar form. Recently it has been demonstrated that non-fibrillar assemblies of A beta possess electrophysiologic activity, with the corollary that they may produce dementia by disrupting neuronal signaling prior to cell death. We therefore examined the effects of soluble oligomers of A beta(1-42) on long-term potentiation (LTP) and long-term depression (LTD), two cellular models of memory, in the dentate gyrus of rat hippocampal slices. Compared with vehicle controls, slices pre-incubated 60 min in the presence of A beta-derived diffusible ligands (ADDLs) showed no differences in threshold intensity to evoke a synaptic response, slope of field excitatory post-synaptic potentials (EPSPs), or the input/output function. Tetanus-induced LTP and reversal of LTD were strongly inhibited in ADDLs-treated slices whereas LTD was unaffected. These data suggest that soluble non-fibrillar amyloid may contribute to the pathogenesis of AD both by impairing LTP/memory formation at the cellular level and by creating 'neuroplasticity imbalance' manifested by unopposed LTD in the setting of impaired capacity for neural repair via reversal of LTD or LTP.
Wang
Hai-Wei
HW
Department of Pediatrics, Northwestern University Medical School and Evanston Hospital, Evanston, IL 60201, USA.
Pasternak
Joseph F
JF
Kuo
Helen
H
Ristic
Helen
H
Lambert
Mary P
MP
Chromy
Brett
B
Viola
Kirsten L
KL
Klein
William L
WL
Stine
W Blaine
WB
Krafft
Grant A
GA
Trommer
Barbara L
BL
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D018891:Dentate Gyrus / Q000502:physiology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects*; D009473:Neuronal Plasticity / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013569:Synapses / Q000502:physiology
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)