Protective Alzheimer's disease-associated APP A673T variant predominantly decreases sAPPß levels in cerebrospinal fluid and 2D/3D cell culture models.

The rare A673T variant was the first variant found within the amyloid precursor protein (APP) gene conferring protection against Alzheimer's disease (AD). Thereafter, different studies have discovered that the carriers of the APP A673T variant show reduced levels of amyloid beta (Aß) in the plasma and better cognitive performance at high age. Here, we analyzed cerebrospinal fluid (CSF) and plasma of APP A673T carriers and control individuals using a mass spectrometry-based proteomics approach to identify differentially regulated targets in an unbiased manner. Furthermore, the APP A673T variant was introduced into 2D and 3D neuronal cell culture models together with the pathogenic APP Swedish and London mutations. Consequently, we now report for the first time the protective effects of the APP A673T variant against AD-related alterations in the CSF, plasma, and brain biopsy samples from the frontal cortex. The CSF levels of soluble APPß (sAPPß) and Aß42 were significantly decreased on average 9-26% among three APP A673T carriers as compared to three well-matched controls not carrying the protective variant. Consistent with these CSF findings, immunohistochemical assessment of cortical biopsy samples from the same APP A673T carriers did not reveal Aß, phospho-tau, or p62 pathologies. We identified differentially regulated targets involved in protein phosphorylation, inflammation, and mitochondrial function in the CSF and plasma samples of APP A673T carriers. Some of the identified targets showed inverse levels in AD brain tissue with respect to increased AD-associated neurofibrillary pathology. In 2D and 3D neuronal cell culture models expressing APP with the Swedish and London mutations, the introduction of the APP A673T variant resulted in lower sAPPß levels. Concomitantly, the levels of sAPPα were increased, while decreased levels of CTFß and Aß42 were detected in some of these models. Our findings emphasize the important role of APP-derived peptides in the pathogenesis of AD and demonstrate the effectiveness of the protective APP A673T variant to shift APP processing towards the non-amyloidogenic pathway in vitro even in the presence of two pathogenic mutations.

Solvation oscillations and excited-state dynamics of 2-amino- and 2-hydroxy-7-nitrofluorene and its 2'-deoxyriboside.

Push-pull substituted fluorenes are considered for use as dynamic solvation probes in polynucleotides. Their fluorescence band is predicted (by simulations) to show weak spectral oscillations on the subpicosecond time scale depending on the nucleotide sequence. The oscillations reflect the local far-infrared spectrum of the environment around the probe molecule. A connection is provided by the continuum theory of polar solvation which, however, neglects molecular aspects. We examine the latter using acetonitrile solution as a test case. A collective librational solvent mode at 100 cm(-1) is observed with 2-amino-7-nitrofluorene, 2-dimethylamino-7-nitrofluorene, 2-hydroxy-7-nitrofluorene, and its 2'-deoxyriboside. Different strengths of the oscillation indicate that rotational friction of nearby acetonitrile molecules depends on the solute structure or that H bonding is involved in launching the librational coherence. Polar solvation in methanol is used for comparison. With hydroxynitrofluorenes, the observation window is limited by intersystem crossing for which rates are reported. A prominent excited-state absorption band of nitrofluorenes at 430 nm can be used to monitor polar solvation. Structural and electronic relaxation pathways are discussed with the help of quantum chemical calculations.