Autoantibody-catalyzed hydrolysis of amyloid ß peptide

We describe IgM class human autoantibodies that hydrolyze amyloid ß peptide 1-40 (Aß40). A monoclonal IgM from a patient with Waldenström's macroglobulinemia hydrolyzed Aß40 at the Lys-28 - Gly-29 bond and Lys-16 - Ala-17 bonds. The catalytic activity was inhibited stoichiometrically by an electrophilic serine protease inhibitor. Treatment with the catalytic IgM blocked the aggregation and toxicity of Aß40 in neuronal cell cultures. IgMs purified from the sera of patients with Alzheimer disease (AD) hydrolyzed Aß40 at rates superior to IgMs from age-matched humans without dementia. IgMs from non-elderly humans expressed the least catalytic activity. The reaction rate was sufficient to afford appreciable degradation at physiological Aß and IgM concentrations found in peripheral circulation. Increased Aß concentrations in the AD brain are thought to induce neurodegenerative effects. Peripheral administration of Aß binding antibodies has been suggested as a potential treatment of AD. Our results suggest that catalytic IgM autoantibodies can help clear Aß, and they open the possibility of using catalytic Abs for AD immunotherapy. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc

Generalization of amygdala LTP and conditioned fear in the absence of presynaptic inhibition

Pavlovian fear conditioning, a simple form of associative learning, is thought to involve the induction of associative, NMDA receptor-dependent long-term potentiation (LTP) in the lateral amygdala. Using a combined genetic and electrophysiological approach, we show here that lack of a specific GABA(B) receptor subtype, GABA(B(1a,2)), unmasks a nonassociative, NMDA receptor-independent form of presynaptic LTP at cortico-amygdala afferents. Moreover, the level of presynaptic GABA(B(1a,2)) receptor activation, and hence the balance between associative and nonassociative forms of LTP, can be dynamically modulated by local inhibitory activity. At the behavioral level, genetic loss of GABA(B(1a)) results in a generalization of conditioned fear to nonconditioned stimuli. Our findings indicate that presynaptic inhibition through GABA(B(1a,2)) receptors serves as an activity-dependent constraint on the induction of homosynaptic plasticity, which may be important to prevent the generalization of conditioned fear

Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk

We performed a meta-analysis of five genome-wide association studies to identify common variants influencing colorectal cancer (CRC) risk comprising 8,682 cases and 9,649 controls. Replication analysis was performed in case-control sets totaling 21,096 cases and 19,555 controls. We identified three new CRC risk loci at 6p21 (rs1321311, near CDKN1A; P = 1.14 × 10 -10), 11q13.4 (rs3824999, intronic to POLD3; P = 3.65 × 10 -10) and Xp22.2 (rs5934683, near SHROOM2; P = 7.30 × 10 -10) This brings the number of independent loci associated with CRC risk to 20 and provides further insight into the genetic architecture of inherited susceptibility to CRC.</p