Studies suggest that dysfunction of brain-derived neurotrophic factor (BDNF) is a possible contributor to the pathology and symptoms of Alzheimer's disease (AD). Several studies report reduced peripheral blood levels of BDNF in AD, but findings are inconsistent. This study sought to quantitatively summarize the clinical BDNF data in patients with AD and mild cognitive impairment (MCI, a prodromal stage of AD) with a meta-analytical technique. A systematic search of Pubmed, PsycINFO and the Cochrane Library identified 29 articles for inclusion in the meta-analysis. Random-effects meta-analysis showed that patients with AD had significantly decreased baseline peripheral blood levels of BDNF compared with healthy control (HC) subjects (24 studies, Hedges' g=-0.339, 95% confidence interval (CI)=-0.572 to -0.106, P=0.004). MCI subjects showed a trend for decreased BDNF levels compared with HC subjects (14 studies, Hedges' g=-0.201, 95% CI=-0.413 to 0.010, P=0.062). No differences were found between AD and MCI subjects in BDNF levels (11 studies, Hedges' g=0.058, 95% CI=-0.120 to 0.236, P=0.522). Interestingly, the effective sizes and statistical significance improved after excluding studies with reported medication in patients (between AD and HC: 18 studies, Hedges' g=-0.492, P<0.001; between MCI and HC: 11 studies, Hedges' g=-0.339, P=0.003). These results strengthen the clinical evidence that AD or MCI is accompanied by reduced peripheral blood BDNF levels, supporting an association between the decreasing levels of BDNF and the progression of AD.

Yapsin 1, a novel aspartic protease with unique specificity for basic residues, was shown to cleave CCK13-33 at Lys23. Molecular modeling of yapsin 1 identified the active-site cleft to have negative residues close to or within the S6, S3, S2, S1, S1', S2', and S3' pockets and is more electronegative than rhizopuspepsin or endothiapepsin. In particular, the S2' subsite has three negative charges in and close to this pocket that can provide strong electrostatic interactions with a basic residue. The model, therefore, predicts that substrates with a basic residue in the P1 position would be favored with additional basic residues binding to the other electronegative pockets. A deletion of six residues close to the S1 pocket in yapsin 1, relative to rhizopuspepsin and other aspartic proteases of known 3D structure, is likely to affect its specificity. The model was tested using CCK13-33 analogues. We report that yapsin 1 preferentially cleaves a CCK13-33 substrate with a basic residue in the P1 position since the substrates with Ala in P1 were not cleaved. Furthermore, the cleavage efficiency of yapsin 1 was enhanced for CCK13-33 analogues with arginine residues flanking the P1 position. An alanine residue, substituting for the arginine residue in the P6 position in CCK13-33, resulted in a 50% reduction in the cleavage efficiency. Substitution with arginine residues downstream of the cleavage site at the P2', P3', or P6' position increased the cleavage efficiency by 21-, 3- and 7-fold, respectively. Substitution of Lys23 in CCK13-33 with arginine resulted not only in cleavage after the substituted arginine residue, but also forced a cleavage after Met25, suggesting that an arginine residue in the S2' pocket is so favorable that it can affect the primary specificity of yapsin 1. These results are consistent with the predictions from the molecular model of yapsin 1.

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