PBT2 is a copper/zinc ionophore that rapidly restores cognition in mouse models of Alzheimer's disease (AD). A recent Phase IIa double-blind, randomized, placebo-controlled trial found that the 250 mg dose of PBT2 was well-tolerated, significantly lowered cerebrospinal fluid (CSF) levels of amyloid-beta42, and significantly improved executive function on a Neuro-psychological Test Battery (NTB) within 12 weeks of treatment in patients with AD. In the post-hoc analysis reported here, the cognitive, blood marker, and CSF neurochemistry outcomes from the trial were subjected to further analysis. Ranking the responses to treatment after 12 weeks with placebo, PBT2 50 mg, and PBT2 250 mg revealed that the proportions of patients showing improvement on NTB Composite or Executive Factor z-scores were significantly greater in the PBT2 250 mg group than in the placebo group. Receiver-operator characteristic analyses revealed that the probability of an improver at any level coming from the PBT2 250 mg group was significantly greater, compared to placebo, for Composite z-scores (Area Under the Curve [AUC] =0.76, p=0.0007), Executive Factor z-scores (AUC =0.93, p=1.3 x 10(-9)), and near-significant for the ADAS-cog (AUC =0.72, p=0.056). There were no correlations between changes in CSF amyloid-beta or tau species and cognitive changes. These findings further encourage larger-scale testing of PBT2 for AD.

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Transgenic expression of human amyloid ␤ (A␤) peptide in body wall muscle cells of Caenorhabditis elegans has been used to better understand aspects of Alzheimer disease (AD). In human aging and AD, A␤ undergoes post-translational changes including covalent modifications, truncations, and oligomerization. Amino truncated A␤ is increasingly recognized as potentially contributing to AD pathogenesis. Here we describe surface-enhanced laser desorption ionization-time of flight mass spectrometry mass spectrometry of A␤ peptide in established transgenic C. elegans lines. Surprisingly, the A␤ being expressed is not full-length 1-42 (amino acids) as expected but rather a 3-42 truncation product. In vitro analysis demonstrates that A␤ 3-42 self-aggregates like A␤ 1-42 , but more rapidly, and forms fibrillar structures. Similarly, A␤ 3-42 is also the more potent initiator of A␤ 1-40 aggregation. Seeded aggregation via A␤ 3-42 is further enhanced via co-incubation with the transition metal Cu(II). Although unexpected, the C. elegans model of A␤ expression can now be co-opted to study the proteotoxic effects and processing of A␤ 3-42 .Numerous studies support a role for aggregating A␤ 3 in mediating the toxicity that underlies AD (1, 2). However, several key questions remain central to understanding how AD and A␤ pathology are related. What is the connection between A␤ aggregation and toxicity? Is there a specific toxic A␤ conformation or species? How and why does aging impact on A␤ precipitation? Significant effort to address these questions has been invested in the use of vertebrate and simple invertebrate model organisms to simulate neurodegenerative diseases through transgenic expression of human A␤ (3). From these models, several novel insights into the proteotoxicity of A␤ have been gained (4 -7).Human A␤ (e.g. in brain, cerebrospinal fluid, or plasma) is not found as a single species but rather as diverse mixtures of various modified, truncated, and cross-linked forms (8 -10). Specific truncations, covalent modifications, and cross-linked oligomers of A␤ have potentially important roles in determining A␤-associated neurotoxicity. For example, N-terminal truncations of A␤ have increased abundance in AD, rapidly aggregate, and are neurotoxic (9, 11). Furthermore, the N-terminal glutamic acid residue of A␤ 3-42 can be cyclized to pyroglutamate (A␤ 3(pE)-42 ) (12), which may be particularly important in AD pathogenesis (13,14). A␤ 3(pE)-42 is a significant fraction of total A␤ in AD brain (15), accounting for more than 50% of A␤ accumulated in plaques (16). A␤ 3(pE)-42 seeds A␤ aggregation (17), confers proteolytic resistance, and is neurotoxic (13). Recently, glutaminyl cyclase (QC) has been proposed to catalyze, in vivo, pyroglutamate formation of A␤ 3(pE)-40/42 (14, 18). A␤ 1-42 itself cannot be cyclized by QC to A␤ 3(pE)-42 (19), unlike A␤ that commences with an N-terminal glutamic acid-residue (e.g. A␤ 3-42 and A␤ 11-42 ) (20). QC has broad expression in mammalian brain (21,22), and its inhibition attenuates accumul...