Amyloid- (A) peptide is thought to have a significant role in the progressive memory loss observed in patients with Alzheimer disease and inhibits synaptic plasticity in animal models of learning. We previously demonstrated that brain-derived neurotrophic factor (BDNF) is critical for synaptic AMPA receptor delivery in an in vitro model of eyeblink classical conditioning. Here, we report that acquisition of conditioned responses was significantly attenuated by bath application of oligomeric (200 nM), but not fibrillar, A peptide. Western blotting revealed that BDNF protein expression during conditioning is significantly reduced by treatment with oligomeric A, as were phosphorylation levels of cAMP-response element-binding protein (CREB), Ca 2؉ /calmodulin-dependent protein kinase II (CaMKII), Ca 2؉ / calmodulin-dependent protein kinase IV (CaMKIV), and ERK. However, levels of PKA and PKC/ were unaffected, as was PDK-1. Protein localization studies using confocal imaging indicate that oligomeric A, but not fibrillar or scrambled forms, suppresses colocalization of GluR1 and GluR4 AMPA receptor subunits with synaptophysin, indicating that trafficking of these subunits to synapses during the conditioning procedure is blocked. In contrast, coapplication of BDNF with oligomeric A significantly reversed these findings. Interestingly, a tolloid-like metalloproteinase in turtle, tTLLs (turtle tolloid-like protein), which normally processes the precursor proBDNF into mature BDNF, was found to degrade oligomeric A into small fragments. These data suggest that an A-induced reduction in BDNF, perhaps due to interference in the proteolytic conversion of proBDNF to BDNF, results in inhibition of synaptic AMPA receptor delivery and suppression of the acquisition of conditioning.
Alzheimer disease (AD)2 is a neurodegenerative disorder resulting in a progressive decline in cognitive function and is characterized pathologically by the presence of senile plaques and intracellular neurofibrillary tangles. Amyloid- peptides (A), the peptide deposited as amyloid plaques, have long been implicated as an important component underlying neural dysfunction associated with AD. Recent evidence indicates that soluble forms of A, such as small and large oligomers that are accumulated before plaque formation, contribute significantly to the pathogenesis of AD by producing excitatory synaptic dysfunction, although the mechanisms are poorly understood (1). Postsynaptic AMPA receptor number and trafficking may be a prime target in AD. A recent study using double knock-in mice carrying mutated human amyloid precursor protein (APP) and presenilin-1 genes exhibited a reduction in AMPA receptor number and AMPA receptor-mediated synaptic currents in CA1 hippocampal neurons that strongly corresponded with increased age, A levels, and plaque deposition (2). Moreover, the double knock-in mice showed age-related deficits in long term potentiation, long term depression, and memory performance. Working memory and spatial learning assessed with t...