O2‐02–02: Soluble amyloid β‐protein dimers isolated directly from Alzheimer's disease patients potently impair synaptic plasticity and memory

Soluble Oligomers of Amyloid β Protein Facilitate Hippocampal Long-Term Depression by Disrupting Neuronal Glutamate Uptake

“…Small, soluble Aβ assemblies have been obtained from a variety of sources, including synthetic peptides, cell culture medium, and human brain extracts (Lambert et al, 1998; Podlisny et al, 1995; McLean et al, 1999; Shankar et al, 2008). A common feature among the soluble Aβ preparations used in the current study is the presence of low-n assembly forms, i.e., Aβ oligomers, that are slightly larger than the monomer but much smaller than amyloid fibrils.…”

“…1A). We recently reported that soluble oligomers extracted directly from human (AD) cortex facilitate LTD induction through activation of mGluR when a subthreshold (300 pulses, 1 Hz) stimulation is applied to hippocampal slices (Shankar et al, 2008). To investigate the mechanisms underlying the enhancement of LTD by soluble human Aβ, we first used cell-secreted Aβ species obtained from a CHO cell line that stably expresses hAPP with the V717F amyloidogenic AD mutation (7PA2 cells).…”

“…The procedures for the hippocampal slice preparation and field excitatory postsynaptic potentials (fEPSPs) recordings in the CA1 region of mouse hippocampus were described previously (Li et al, 2006; Shankar et al, 2008). A bipolar stimulating electrode (FHC Inc., Bowdoin, ME) was placed in the Schaffer collaterals to deliver test and conditioning stimuli.…”

“…Of note, dementia severity in AD correlates more strongly with cortical levels of soluble Aβ species than with insoluble amyloid plaque burden (Lue et al, 1999; McLean et al, 1999). Experimentally, soluble Aβ oligomers have been specifically shown to block hippocampal long-term potentiation (LTP), an electrophysiological correlate of learning and memory (e.g., Lambert et al, 1998; Walsh et al, 2002; Wang et al, 2002; Townsend et al, 2006; Shankar et al, 2008). In accord, impairment of synaptic plasticity can be detected in vivo before the formation of insoluble Aβ deposits in APP transgenic mouse models (e.g., Hsia et al, 1999; Mucke et al, 2000).…”

“…For example, synthetic Aβ peptides were reported to facilitate LTD induction in an NMDAR-dependent manner in vivo (Kim at al., 2001), whereas other studies found no effect on LTD in slices (Raymond et al, 2003; Wang et al, 2002; 2004a). We recently extracted buffer-soluble Aβ directly from the brains of typical AD patients and showed that this extract, which contains soluble Aβ dimers and trimers, facilitated LTD induction in the CA1 region of mouse hippocampus by an mGluR-dependent mechanism (Shankar et al, 2008). Given that both NMDAR and mGluR activation have been implicated in the effects of Aβ on LTD, we asked whether glutamate clearance mechanisms are perturbed by Aβ.…”