. Oligomeric amyloid-{beta} inhibits the proteolytic conversion of brain-derived neurotrophic factor (BDNF), AMPA receptor trafficking, and classical conditioning. J Biol Chem. 2010 Nov 5;285(45):34708-17. PubMed.


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  1. Aβ-induced deficits in synaptic function are well documented, but the mechanisms have been uncertain. Literature supports effects of Aβ on both BDNF and on AMPA receptors, but it has not been clear whether or how these mechanisms are linked. This well-designed and thorough study from the Keifer lab shows that BDNF mediates Aβ’s effect on AMPA receptor trafficking to synapses. This group has previously shown that Aβ conditioning activates several kinases including PKA, PKC, CaMKII, and CaMKIV, resulting in CREB activation, BDNF expression, and activation of ERK to trigger AMPA receptor synaptic delivery. In this paper, a subset of the same pathway is identified as affected by Aβ (PKA and PKC are not affected). An experiment in which Aβ-induced reduction in GluR1- and GluR4-containing AMPA receptor synaptic delivery is rescued by recombinant BDNF places AMPA receptor trafficking firmly downstream of BDNF in this pathway.

    It has previously been shown in vitro that oligomeric Aβ, but not the less toxic fibrillar form, reduces BDNF activity by decreasing CREB-mediated BDNF expression and by decreasing BDNF signaling downstream of its receptor, TrkB (see Tong et al., 2001; Tong et al., 2004; Garzon and Fahnestock, 2007). The current paper adds a significant new mechanism by which oligomeric Aβ inhibits BDNF action, by reducing processing of proBDNF to mature BDNF. This mechanism is supported by work showing that BDNF is more sharply reduced than proBDNF in MCI and AD brain (Peng et al., 2005). Interestingly, the mechanism of the proteolytic inhibition reported here is competition between Aβ and proBDNF for the processing enzyme, turtle tolloid-like metalloprotease (tTTLs). This is different from the mechanism that has been described previously: in the Alzheimer’s brain, neuroserpin levels are elevated, which inhibits tissue plasminogen activator activity and leads to reduced plasmin (Fabbro and Seeds, 2009), the enzyme which processes proBDNF to BDNF (Pang et al., 2004). Other metalloproteases such as matrix metalloproteases 3 and 7 are capable of processing proBDNF in vitro (Lee et al., 2001), but whether a human enzyme similar to tTTLs also processes proBDNF and might contribute to reduced BDNF in the Alzheimer’s brain is unknown.


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