Comprehensive binary interaction mapping of τ phosphotyrosine sites with SH2 domains in the human genome: Implications for the rational design of self-inhibitory phosphopeptides to target τ hyperphosphorylation signaling in Alzheimer's Disease.

Human microtubule-associated protein Tau (τ) is abundant in the axons of neurons where it stabilizes microtubule bundles; abnormally hyperphosphorylated τ is a hallmark of Alzheimer's disease (AD) and related tauopathies. The hyperphosphorylation events can be recognized by phosphotyrosine-recognition domain SH2 (Src homology 2) to elicit downstream τ signaling in AD pathology. In this study, a comprehensive binary interaction map (CBIM) of all the 6 τ phosphotyrosine sites with 120 SH2 domains in the human genome was systematically created at structural level using computational analyses and binding assays, from which we were able to identify those of strong and moderate binding pairs of sites to domains.

Computational systematic selectivity of the Fasalog inhibitors between ROCK-I and ROCK-II kinase isoforms in Alzheimer's disease.

Human Rho-associated coiled-coil forming kinase (ROCK) is a class of essential neurokinases that consists of two structurally conserved isoforms ROCK-I and ROCK-II; they have been revealed to play distinct roles in the pathogenesis of Alzheimer's disease (AD) and other neurological disorders. Selective targeting of the two kinase isoforms with small-molecule inhibitors is a great challenge due to the surprisingly high homology in kinase domain (92 %) and the full identity in kinase active site (100 %). Here, we describe a computational protocol to systematically profile the selectivity of Fasudil and its 25 analogs (termed as Fasalogs) between the two kinase isoforms.

Dihydrotanshinone I Increase Amyloid-β Clearance and Decrease Tau Phosphorylation via Enhancing Autophagy.

Introduction: The plaques formed by amyloid-β (Aβ) accumulation and neurofibrillary tangles formed by hyper-phosphorylated tau protein are the 2 major pathologies of Alzheimer's disease (AD). Recently, autophagy is considered to be a self-degradation process of preserved cytoplasmic abnormal substances, including Aβ and tau.

Methods: α-Screen assay is used to discover a new mammalian target of rapamycin (mTOR) signaling inhibitor, and laser scanning confocal microscopic analysis is used to investigate the autophagy formation.

Overexpression of MicroRNA-9a-5p Ameliorates NLRP1 Inflammasome-mediated Ischemic Injury in Rats Following Ischemic Stroke.

The nucleotide oligomerization domain (NOD)-like receptor (NLR) pyrin domain-containing protein 1 (NLRP1) inflammasome has been shown to contribute to brain injury after ischemic stroke. Our previous study showed that microRNA-9a-5p (miR-9a-5p) ameliorates ischemic injury by regulating neuronal autophagy in rats subjected to middle cerebral artery occlusion (MCAO) surgery. The aims of this study were to investigate whether miR-9a-5p can influence the NLRP1 inflammasome following ischemic stroke and to clarify the mechanism involved.