Alzheimer's disease brain-derived amyloid-ß-mediated inhibition of LTP in vivo is prevented by immunotargeting cellular prion protein.

Synthetic amyloid-ß protein (Aß) oligomers bind with high affinity to cellular prion protein (PrP(C)), but the role of this interaction in mediating the disruption of synaptic plasticity by such soluble Aß in vitro is controversial. Here we report that intracerebroventricular injection of Aß-containing aqueous extracts of Alzheimer's disease (AD) brain robustly inhibits long-term potentiation (LTP) without significantly affecting baseline excitatory synaptic transmission in the rat hippocampus in vivo. Moreover, the disruption of LTP was abrogated by immunodepletion of Aß. Importantly, intracerebroventricular administration of antigen-binding antibody fragment D13, directed to a putative Aß-binding site on PrP(C), prevented the inhibition of LTP by AD brain-derived Aß. In contrast, R1, a Fab directed to the C terminus of PrP(C), a region not implicated in binding of Aß, did not significantly affect the Aß-mediated inhibition of LTP. These data support the pathophysiological significance of SDS-stable Aß dimer and the role of PrP(C) in mediating synaptic plasticity disruption by soluble Aß.

Alzheimer's disease amyloid beta-protein and synaptic function.

Alzheimer's disease (AD) is characterized neuropathologically by the deposition of different forms of amyloid beta-protein (A beta) including variable amounts of soluble species that correlate with severity of dementia. The extent of synaptic loss in the brain provides the best morphological correlate of cognitive impairment in clinical AD. Animal research on the pathophysiology of AD has therefore focussed on how soluble A beta disrupts synaptic mechanisms in vulnerable brain regions such as the hippocampus. Synaptic plasticity in the form of persistent activity-dependent increases or decreases in synaptic strength provide a neurophysiological substrate for hippocampal-dependent learning and memory. Acute treatment with human-derived or chemically prepared soluble A beta that contains certain oligomeric assemblies, potently and selectively disrupts synaptic plasticity causing inhibition of long-term potentiation (LTP) and enhancement of long-term depression (LTD) of glutamatergic transmission. Over time these and related actions of A beta have been implicated in reducing synaptic integrity. This review addresses the involvement of neurotransmitter intercellular signaling in mediating or modulating the synaptic plasticity disrupting actions of soluble A beta, with particular emphasis on the different roles of glutamatergic and cholinergic mechanisms. There is growing evidence to support the view that NMDA and possibly nicotinic receptors are critically involved in mediating the disruptive effect of A beta and that targeting muscarinic receptors can indirectly modulate A beta's actions. Such studies should help inform ongoing and future clinical trials of drugs acting through the glutamatergic and cholinergic systems.