Alzheimer’s disease is characterized by accumulation of amyloid plaques and tau aggregates in several cortical brain regions. Tau phosphorylation causes formation of neurofibrillary tangles and neuropil threads. Phosphorylation at tau Ser202/Thr205 is well characterized since labeling of this site is used to assign Braak stage based on occurrence of neurofibrillary tangles. Only little is known about the spatial and temporal phosphorylation profile of other phosphorylated tau (ptau) sites. Here, we investigate total tau and ptau at residues Tyr18, Ser199, Ser202/Thr205, Thr231, Ser262, Ser396, Ser422 as well as amyloid-β plaques in human brain tissue of AD patients and controls. Allo- and isocortical brain regions were evaluated applying rater-independent automated quantification based on digital image analysis. We found that the level of ptau at several residues, like Ser199, Ser202/Thr205, and Ser422 was similar in healthy controls and Braak stages I to IV but was increased in Braak stage V/VI throughout the entire isocortex and transentorhinal cortex. Quantification of ThioS-stained plaques showed a similar pattern. Only tau phosphorylation at Tyr18 and Thr231 was already significantly increased in the transentorhinal region at Braak stage III/IV and hence showed a progressive increase with increasing Braak stages. Additionally, the increase in phosphorylation relative to controls was highest at Tyr18, Thr231 and Ser199. By contrast, Ser396 tau and Ser262 tau showed only a weak phosphorylation in all analyzed brain regions and only minor progression. Our results suggest that the ptau burden in the isocortex is comparable between all analyzed ptau sites when using a quantitative approach while levels of ptau at Tyr18 or Thr231 in the transentorhinal region are different between all Braak stages. Hence these sites could be crucial in the pathogenesis of AD already at early stages and therefore represent putative novel therapeutic targets.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0557-6) contains supplementary material, which is available to authorized users.

Neurofilament-light chain (NF-L) is a well-known clinical biomarker of many neurodegenerative diseases. By analyzing amyotrophic lateral sclerosis (ALS) patients cerebrospinal fluid (CSF) or plasma, progression of NF-L levels can forecast conversion from the presymptomatic to symptomatic stage and time of survival. The use of plasma for NF-L measurement makes this biomarker exceptionally valuable for clinical studies since sample collection can be performed repeatedly without causing much harm. Detailed analyses of NF-L expression in neurodegenerative disease patient's samples were already performed, while NF-L levels of preclinical models of ALS, Alzheimer's and Parkinson's disease as well as lysosomal storage diseases are still widely unknown. We therefore evaluated NF-L levels in the plasma of the ALS models SOD1-G93A low expressor and TAR6/6 mice, the Alzheimer's disease (AD) model 5xFAD, the Parkinson's disease model Line 61 and the Gaucher disease (GD) model 4L/PS-NA and the CSF of selected models. Our results show that NF-L levels are highly increased in the plasma of ALS, Alzheimer's and GD models, while in the analyzed Parkinson's disease model NF-L plasma levels barely changed. Most analyzed models show a progressive increase of NF-L levels. NF-L measurements in the plasma of the neurodegenerative disease mouse models of ALS and AD are thus a good tool to evaluate disease progression. Compared to analyses in human tissues, our results suggest a high translation value of murine NF-L levels and their progression. Furthermore, our data indicate that NF-L might also be a good biomarker for disorders with a neuronal component like some lysosomal storage diseases.

The orally administered topical active steroid budesonide is highly effective in the therapy of loperamide-refractory chemotherapy (CPT-11 or 5-FU)-induced diarrhea.

We evaluated the hypothesis that phosphodiesterase-5 inhibitors, including sildenafil and tadalafil, may be associated with reduced incidence of Alzheimer’s disease and related dementia using a patient-level cohort study of Medicare claims and cell culture-based phenotypic assays. We compared incidence of Alzheimer’s disease and related dementia after phosphodiesterase-5 inhibitor initiation versus endothelin receptor antagonist initiation among patients with pulmonary hypertension after controlling for 76 confounding variables through propensity-score matching. Across 4 separate analytic approaches designed to address specific types of biases including informative censoring, reverse causality, and outcome misclassification, we observed no evidence for a reduced risk of Alzheimer’s disease and related dementia with after phosphodiesterase-5 inhibitors with hazard ratio [95% confidence interval] of 0.99 [0.69-1.43], 1.00 [0.71-1.42], 0.67 [0.43-1.06], and 1.15 [0.57-2.34]. We also did not observe evidence that sildenafil ameliorated molecular abnormalities relevant to Alzheimer’s disease in most cell culture-based phenotypic assays. These results do not provide support to the hypothesis that phosphodiesterase-5 inhibitors are promising repurposing candidates for Alzheimer’s disease and related dementia.

Brain proteins altered in young APOE ε4 carriers are found decades later in Alzheimer’s disease and present novel drug targets.