Molecular engineering of a theranostic molecule that detects Aβ plaques, inhibits Iowa and Dutch mutation Aβ self-aggregation and promotes lysosomal biogenesis for Alzheimer's disease.

Extracellular clustering of amyloid-β (Aβ) and an impaired autophagy lysosomal pathway (ALP) are the hallmark features in the early stages of incurable Alzheimer's disease (AD). There is a pressing need to find or develop new small molecules for diagnostics and therapeutics for the early stages of AD. Herein, we report a small molecule, namely F-SLCOOH, which can bind and detect Aβ, Iowa mutation Aβ, Dutch mutation Aβ fibrils and oligomers exhibiting enhanced emission with high affinity.

Corynoxine promotes TFEB/TFE3-mediated autophagy and alleviates Aβ pathology in Alzheimer's disease models.

Autophagy impairment is a key factor in Alzheimer's disease (AD) pathogenesis. TFEB (transcription factor EB) and TFE3 (transcription factor binding to IGHM enhancer 3) are nuclear transcription factors that regulate autophagy and lysosomal biogenesis. We previously showed that corynoxine (Cory), a Chinese medicine compound, protects neurons from Parkinson's disease (PD) by activating autophagy.

Fe65-engineered neuronal exosomes encapsulating corynoxine-B ameliorate cognition and pathology of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the predominant impairment of neurons in the hippocampus and the formation of amyloid plaques, hyperphosphorylated tau protein, and neurofibrillary tangles in the brain. The overexpression of amyloid-β precursor protein (APP) in an AD brain results in the binding of APP intracellular domain (AICD) to Fe65 protein via the C-terminal Fe65-PTB2 interaction, which then triggers the secretion of amyloid-β and the consequent pathogenesis of AD. Apparently, targeting the interaction between APP and Fe65 can offer a promising therapeutic approach for AD.

PPARɑ Ligand Caudatin Improves Cognitive Functions and Mitigates Alzheimer's Disease Defects By Inducing Autophagy in Mice Models.

The autophagy-lysosomal pathway (ALP) is a major cellular machinery involved in the clearance of aggregated proteins in Alzheimer disease (AD). However, ALP is dramatically impaired during AD pathogenesis via accumulation of toxic amyloid beta (Aβ) and phosphorylated-Tau (phospho-Tau) proteins in the brain. Therefore, activation of ALP may prevent the increased production of Aβ and phospho-Tau in AD.

Impact and Advances in the Role of Bacterial Extracellular Vesicles in Neurodegenerative Disease and Its Therapeutics.

Bacterial Extracellular Vesicles (BEVs) possess the capability of intracellular interactions with other cells, and, hence, can be utilized as an efficient cargo for worldwide delivery of therapeutic substances such as monoclonal antibodies, proteins, plasmids, siRNA, and small molecules for the treatment of neurodegenerative diseases (NDs). BEVs additionally possess a remarkable capacity for delivering these therapeutics across the blood-brain barrier to treat Alzheimer's disease (AD). This review summarizes the role and advancement of BEVs for NDs, AD, and their treatment.

Genome-wide CRISPR-Cas9 Knockout Screening Reveals a TSPAN3-mediated Endo-lysosome Pathway Regulating the Degradation of α-Synuclein Oligomers.

Misfolding and aggregation of α-Synuclein (α-Syn), which are hallmark pathological features of neurodegenerative diseases such as Parkinson's disease (PD) and dementia with Lewy Bodies, continue to be significant areas of research. Among the diverse forms of α-Syn - monomer, oligomer, and fibril, the oligomer is considered the most toxic. However, the mechanisms governing α-Syn oligomerization are not yet fully understood.

Bromo-protopine, a novel protopine derivative, alleviates tau pathology by activating chaperone-mediated autophagy for Alzheimer's disease therapy.

Emerging evidence from Alzheimer's disease (AD) patients suggests that reducing tau pathology can restore cognitive and memory loss. To reduce tau pathology, it is critical to find brain-permeable tau-degrading small molecules that are safe and effective. HDAC6 inhibition has long been considered a safe and effective therapy for tau pathology.

Celastrol enhances transcription factor EB (TFEB)-mediated autophagy and mitigates Tau pathology: Implications for Alzheimer's disease therapy.

Alzheimer's disease (AD), characterized by the accumulation of protein aggregates including phosphorylated Tau aggregates, is the most common neurodegenerative disorder with limited therapeutic agents. Autophagy plays a critical role in the degradation of phosphorylated Tau aggregates, and transcription factor EB (TFEB) is a master regulator of autophagy and lysosomal biogenesis. Thus, small-molecule autophagy enhancers targeting TFEB hold promise for AD therapy.

Deep-Learning-Based End-to-End Predictions of CO Capture in Metal-Organic Frameworks.

Metal-organic frameworks (MOFs) have become an active topic because of their excellent carbon capture and storage (CCS) properties. However, it is quite challenging to identify MOFs with superior performance within a massive combinatorial search space. To this end, we propose a deep-learning-based end-to-end prediction model to rapidly and accurately predict the CO working capacity and CO/N selectivity of a given MOF under low-pressure conditions.

Mechanistic Insights into Selective Autophagy Subtypes in Alzheimer's Disease.

Eukaryotic cells possess a plethora of regulatory mechanisms to maintain homeostasis and ensure proper biochemical functionality. Autophagy, a central, conserved self-consuming process of the cell, ensures the timely degradation of damaged cellular components. Several studies have demonstrated the important roles of autophagy activation in mitigating neurodegenerative diseases, especially Alzheimer's disease (AD).

Klotho an Autophagy Stimulator as a Potential Therapeutic Target for Alzheimer's Disease: A Review.

Alzheimer's disease (AD) is an age-associated neurodegenerative disease; it is the most common cause of senile dementia. Klotho, a single-pass transmembrane protein primarily generated in the brain and kidney, is active in a variety of metabolic pathways involved in controlling neurodegeneration and ageing. Recently, many studies have found that the upregulation of Klotho can improve pathological cognitive deficits in an AD mice model and have demonstrated that Klotho plays a role in the induction of autophagy, a major contributing factor for AD.

Corynoxine B derivative CB6 prevents Parkinsonian toxicity in mice by inducing PIK3C3 complex-dependent autophagy.

Increasing evidence shows that autophagy impairment is involved in the pathogenesis and progression of neurodegenerative diseases including Parkinson's disease (PD). We previously identified a natural alkaloid named corynoxine B (Cory B) as a neuronal autophagy inducer. However, its brain permeability is relatively low, which hinders its potential use in treating PD.

Protopine promotes the proteasomal degradation of pathological tau in Alzheimer's disease models via HDAC6 inhibition.

Background: Collective evidences have indicated that intracellular accumulation of hyperphosphorylated tau forms neurofibrillary tangles in the brain, which impairs memory, cognition and affects social activities in Alzheimer's disease (AD).

Purpose: To investigate the tau-reducing, and memory-enhancing properties of protopine (PRO), a natural alkaloid isolated from Chinese herbal medicine Corydalis yanhusuo (Yanhusuo in Chinese).

Study Design: By using Histone deacetylase 6 (HDAC6) profiling and immunoprecipitation assays, we assessed that PRO mediated the heat shock protein 90 (HSP90) chaperonic activities for the degradation of pathological tau in AD cell culture models.

Qingyangshen mitigates amyloid-β and Tau aggregate defects involving PPARα-TFEB activation in transgenic mice of Alzheimer's disease.

Background: Alzheimer's disease (AD) is the most common neurodegenerative disease. Deposition of amyloid β plaques (Aβ) and neurofibrillary tangles (NFTs) is the key pathological hallmark of AD. Accumulating evidence suggest that impairment of autophagy-lysosomal pathway (ALP) plays key roles in AD pathology.

Identification of CYP46A1 as a new regulator of lipid metabolism through CRISPR-based whole-genome screening.

Abnormal lipid droplet (LD) metabolism causes a variety of disorders, especially to nonalcoholic fatty liver disease (NAFLD). But the mechanism of abnormal aggregation of LD is still not fully elucidated. Here, Genome-wide CRISPR-Cas9 knockout (GeCKO) screening was employed to identify candidate genes regulating LD metabolism in L02 cell.

CRISPR/Cas9-mediated whole genomic wide knockout screening identifies mitochondrial ribosomal proteins involving in oxygen-glucose deprivation/reperfusion resistance.

Recanalization therapy by intravenous thrombolysis or endovascular therapy is critical for the treatment of cerebral infarction. However, the recanalization treatment will also exacerbate acute brain injury and even severely threatens human life due to the reperfusion injury. So far, the underlying mechanisms for cerebral ischaemia-reperfusion injury are poorly understood and effective therapeutic interventions are yet to be discovered.

Energy-Level Jumping Algorithm for Global Optimization in Compressive Sensing-Based Target Localization.

Target localization is one of the essential tasks in almost applications of wireless sensor networks. Some traditional compressed sensing (CS)-based target localization methods may achieve low-precision target localization because of using locally optimal sparse solutions. Solving global optimization for the sparse recovery problem remains a challenge in CS-based target localization.

ATP13A2 facilitates HDAC6 recruitment to lysosome to promote autophagosome-lysosome fusion.

Mutations in cause Kufor-Rakeb syndrome, an autosomal recessive form of juvenile-onset atypical Parkinson's disease (PD). Recent work tied to autophagy and other cellular features of neurodegeneration, but how ATP13A2 governs numerous cellular functions in PD pathogenesis is not understood. In this study, the ATP13A2-deficient mouse developed into aging-dependent phenotypes resembling those of autophagy impairment.

Bandwidth Cost Minimization via User Association for Enterprise WLANs.

Enterprise Wireless LANs (E-WLANs) such as airport WiFi, have become a convenient way for Internet access for mobile users. In an E-WLAN, access points (APs) are usually deployed with high-density around the infrastructure to provide sufficient coverage and for a better service, where a mobile user chooses one AP to associate with among multiple available APs in the vicinity. Many studies have been done on developing user association techniques to increase system performance, with various objectives including network throughput maximization, load balancing etc.