The stress response neuropeptide CRF increases amyloid‐β production by regulating γ‐secretase activity

The biological underpinnings linking stress to Alzheimer's disease (AD) risk are poorly understood. We investigated how corticotrophin releasing factor (CRF), a critical stress response mediator, influences amyloid‐β (Aβ) production. In cells, CRF treatment increases Aβ production and triggers CRF receptor 1 (CRFR1) and γ‐secretase internalization. Co‐immunoprecipitation studies establish that γ‐secretase associates with CRFR1; this is mediated by β‐arrestin binding motifs. Additionally, CRFR1 and γ‐secretase co‐localize in lipid raft fractions, with increased γ‐secretase accumulation upon CRF treatment. CRF treatment also increases γ‐secretase activity in vitro, revealing a second, receptor‐independent mechanism of action. CRF is the first endogenous neuropeptide that can be shown to directly modulate γ‐secretase activity. Unexpectedly, CRFR1 antagonists also increased Aβ. These data collectively link CRF to increased Aβ through γ‐secretase and provide mechanistic insight into how stress may increase AD risk. They also suggest that direct targeting of CRF might be necessary to effectively modulate this pathway for therapeutic benefit in AD, as CRFR1 antagonists increase Aβ and in some cases preferentially increase Aβ42 via complex effects on γ‐secretase.     

Diversity in Mediterranean farm ponds: trade‐offs and synergies between irrigation modernisation and biodiversity conservation

1. Agricultural intensification has caused dramatic biodiversity loss in many agricultural landscapes over the last century. Here, we investigated whether new types of farm ponds (made of artificial substrata) in intensive systems and natural‐substratum ponds in traditional farming systems differ in their value for aquatic biodiversity conservation. 2. We analysed the main patterns of environmental variation, compared α‐, β‐ and γ‐diversity of macroinvertebrates between ponds types and evaluated the role of submerged aquatic vegetation (SAV). Generalised additive models (GAM) were used to analyse the relationships of α‐ and β‐diversity with environmental predictors, and variation partitioning to separate the effect of environmental and spatial characteristics on the variation in macroinvertebrate assemblages. Moran’s eigenvector maps (MEMs) were used to define spatial variables. 3. A principal coordinate analysis (PCoA) detected a primary environmental gradient that separated nutrient‐rich ponds from those dominated by SAV; a secondary morphometric gradient distinguished natural‐substratum ponds, with large surface area and structural complexity, from artificial‐substratum ponds with steeper slopes. Natural‐substratum ponds had almost twice the α‐ and γ‐diversity of artificial‐substratum ponds, and diversity significantly increased when SAV was present, particularly in artificial‐substratum ponds. Total phosphorus (TP) strongly contributed to explain the patterns in diversity, while SAV was a significant predictor of assemblage composition and diversity. GAMs revealed optima of both α‐diversity at intermediate SAV covers and β‐diversity at intermediate–high TP concentrations. 4. These findings have important implications for conservation planning. Adaptation of artificial‐substratum ponds by adding natural substratum and smoothing the gradient of pond margins would improve their conservation value. Development of SAV with occasional harvests and certain cautionary measures to control nutrient levels may also improve both the agronomical and environmental function of ponds.