Extracellular interface between APP and Nicastrin regulates Aβ length and response to γ-secretase modulators

γ‐Secretase complexes (GSECs) are multimeric membrane proteases involved in a variety of physiological processes and linked to Alzheimer's disease (AD). Presenilin (PSEN, catalytic subunit), Nicastrin (NCT), Presenilin Enhancer 2 (PEN‐2), and Anterior Pharynx Defective 1 (APH1) are the essential subunits of GSECs. Mutations in PSEN and the Amyloid Precursor Protein (APP) cause early‐onset AD. GSECs successively cut APP to generate amyloid‐β (Aβ) peptides of various lengths. AD‐causing mutations destabilize GSEC‐APP/Aβ_{n} interactions and thus enhance the production of longer Aβs, which elicit neurotoxic events underlying pathogenesis. Here, we investigated the molecular strategies that anchor GSEC and APP/Aβ_{n} during the sequential proteolysis. Our studies reveal that a direct interaction between NCT ectodomain and APP_{C99} influences the stability of GSEC‐Aβn assemblies and thereby modulates Aβ length. The data suggest a potential link between single‐nucleotide variants in NCSTN and AD risk. Furthermore, our work indicates that an extracellular interface between the protease (NCT, PSEN) and the substrate (APP) represents the target for compounds (GSMs) modulating Aβ length. Our findings may guide future rationale‐based drug discovery efforts

Tau protein liquid–liquid phase separation can initiate tau aggregation

Abstract The transition between soluble intrinsically disordered tau protein and aggregated tau in neurofibrillary tangles in Alzheimer's disease is unknown. Here, we propose that soluble tau species can undergo liquid–liquid phase separation (LLPS) under cellular conditions and that phase‐separated tau droplets can serve as an intermediate toward tau aggregate formation. We demonstrate that phosphorylated or mutant aggregation prone recombinant tau undergoes LLPS, as does high molecular weight soluble phospho‐tau isolated from human Alzheimer brain. Droplet‐like tau can also be observed in neurons and other cells. We found that tau droplets become gel‐like in minutes, and over days start to spontaneously form thioflavin‐S‐positive tau aggregates that are competent of seeding cellular tau aggregation. Since analogous LLPS observations have been made for FUS, hnRNPA1, and TDP43, which aggregate in the context of amyotrophic lateral sclerosis, we suggest that LLPS represents a biophysical process with a role in multiple different neurodegenerative diseases

The total protein content, protein fractions and proteases activities of drone prepupae of Apis mellifera due to varrosis

The proteins level and activities of acid and alkaline proteases in whole body extracts of drone prepupae of Apis mellifera naturaly infested with Varroa destructor were studied. The infested and a non-infested group did not differ significantly in their total protein content. However, some differences in protein profiles were found. A lack of three protein fractions of moderate and lower molecular weight in infested prepupae was noted. Moreover, some differences in the quantity of protein in most of the fractions were observed. The activity of acid proteases from infested prepupae was lower (p < 0.05) compared with the activity of these proteases from the non-infested one group. The infested drone had higher activity of alkaline proteases than non-infested but this difference was not statisticaly significant

Composition of fatty acids in the Varroa destructor mites and their hosts, Apis mellifera drone-prepupae

The fatty acid (FA) profile of lipids extracted from the Varroa destructor parasitic mite and its host, drone prepupae of Apis mellifera, was determined by gas chromatography (GC). The percentages of saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) were generally similar in parasites and their hosts. Fatty acids were arranged in the following descending order based on their content: MUFAs (ca. 52–55%), SFAs (ca. 41%) and PUFAs (ca. 3%). The predominant fatty acids were oleic acid (46% in mites, 44% in prepupae) and palmitic acid (23% and 30%, respectively). Varroa parasites differed from their hosts in the quantity of individual FAs and in their FA profiles. Three PUFAs noted in the host were not observed in parasitic mites, whereas the presence of C21:0, C24:0 and C22:1 FAs was reported in mites, but not in drones

Zawartosc trehalozy i aktywnosc trehalazy u larw Galleria mellonella zarazonych Steinernema affinis, Bovien 1937 [Nematoda: Rhabditida: Steinernematidae]

The experimental studies were conducted on caterpillars of wax moth Galleria mellonella infected with Steinernema affinis larvae. The concentration of trehalose and the activity of trehal ase were measured during the invasion lasting 48h. The level of trehalose and activity of enzyme were slightly lower in infected insects in comparison to the control animals

Synapsin 1 promotes A beta generation via BACE1 modulation

It has been revealed that β-amyloid (Aβ) is generated and released from the presynaptic terminals in activity-dependent manner. However, molecules modulating the presynaptic Aβ generation remain elusive. Here we test the hypothesis that Synapsin 1 (Syn1) may acts as a modulator of the Aβ production. Using biochemical and Förster resonance energy transfer (FRET)-based imaging approaches we have found that Syn1 knock down decreases, whereas (over)expression of Syn1 in cells increases the Aβ levels. Mechanistically, Syn1 does not seem to affect the activity of Presenilin 1 (PS1)/γ-secretase, PS1 conformation, or the proximity between PS1 and amyloid precursor protein (APP). However, we found that Syn1 is involved in up-regulation of the β-site APP cleaving enzyme 1 (BACE1)/β-secretase activity and increases the APP/BACE1 interaction. Therefore, we conclude that Syn1 may promote Aβ production via the modulation of BACE1.status: publishe

Synapsin 1 promotes Aβ generation via BACE1 modulation.

It has been revealed that β-amyloid (Aβ) is generated and released from the presynaptic terminals in activity-dependent manner. However, molecules modulating the presynaptic Aβ generation remain elusive. Here we test the hypothesis that Synapsin 1 (Syn1) may acts as a modulator of the Aβ production. Using biochemical and Förster resonance energy transfer (FRET)-based imaging approaches we have found that Syn1 knock down decreases, whereas (over)expression of Syn1 in cells increases the Aβ levels. Mechanistically, Syn1 does not seem to affect the activity of Presenilin 1 (PS1)/γ-secretase, PS1 conformation, or the proximity between PS1 and amyloid precursor protein (APP). However, we found that Syn1 is involved in up-regulation of the β-site APP cleaving enzyme 1 (BACE1)/β-secretase activity and increases the APP/BACE1 interaction. Therefore, we conclude that Syn1 may promote Aβ production via the modulation of BACE1