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Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy
The ε4 allele of the apolipoprotein E (
APOE
) gene is a strong risk factor for late-onset Alzheimer's disease (AD). Bu discusses the contribution of the various APOE isoforms and APOE receptors to the pathophysiology of AD and emerging therapeutic opportunities.
Key Points
Apolipoprotein E4 (APOE4) is the strongest risk factor for sporadic late-onset Alzheimer's disease (AD), which accounts for the vast majority of AD cases.
APOE4 differs from APOE2 and APOE3 at amino acid positions 112 and 158 and has a unique conformation that influences its lipid- and receptor-binding properties.
The cellular functions of APOE are mediated by APOE receptors, which are members of the low-density lipoprotein receptor (LDLR) family. LDLR-related protein 1 (LRP1) and the LDLRs are the two major types of APOE metabolic receptors in the brain.
APOE receptors regulate amyloid precursor protein (APP) trafficking and processing to amyloid-β (Aβ). Some of these functions are further modified by particular APOE isoforms.
APOE and APOE receptors have important roles in Aβ clearance both in the brain parenchyma and in the brain vasculature. APOE3 binds to Aβ more strongly than APOE4, and therefore it is more efficient at mediating Aβ clearance through APOE receptors.
APOE fragments generated from APOE4 influence tau phosphorylation and mitochondrial function. However, the mechanisms of these events are poorly understood.
The primary function of APOE is to transport lipids from astrocytes to neurons, an event that is crucial for synaptogenesis, synaptic repair, dendritic spine integrity and synaptic functions. APOE4 functions less efficiently than APOE3 in these processes.
APOE and APOE receptors are new targets for AD therapy. Several strategies have been reported or proposed.
The vast majority of Alzheimer's disease (AD) cases are late-onset and their development is probably influenced by both genetic and environmental risk factors. A strong genetic risk factor for late-onset AD is the presence of the ɛ4 allele of the apolipoprotein E (
APOE
) gene, which encodes a protein with crucial roles in cholesterol metabolism. There is mounting evidence that APOE4 contributes to AD pathogenesis by modulating the metabolism and aggregation of amyloid-β peptide and by directly regulating brain lipid metabolism and synaptic functions through APOE receptors. Emerging knowledge of the contribution of APOE to the pathophysiology of AD presents new opportunities for AD therapy.
Journal Article
Targeting Wnt/β-Catenin Pathway for Developing Therapies for Hair Loss
Persistent hair loss is a major cause of psychological distress and compromised quality of life in millions of people worldwide. Remarkable progress has been made in understanding the molecular basis of hair loss and identifying valid intracellular targets for designing effective therapies for hair loss treatment. Whereas a variety of growth factors and signaling pathways have been implicated in hair cycling process, the activation of Wnt/β-catenin signaling plays a central role in hair follicle regeneration. Several plant-derived chemicals have been reported to promote hair growth by activating Wnt/β-catenin signaling in various in vitro and in vivo studies. This mini-review sheds light on the role of Wnt/β-catenin in promoting hair growth and the current progress in designing hair loss therapies by targeting this signaling pathway.
Journal Article
Chromatin 3D structure reconstruction with consideration of adjacency relationship among genomic loci
Background
Chromatin 3D conformation plays important roles in regulating gene or protein functions. High-throughout chromosome conformation capture (3C)-based technologies, such as Hi-C, have been exploited to acquire the contact frequencies among genomic loci at genome-scale. Various computational tools have been proposed to recover the underlying chromatin 3D structures from in situ Hi-C contact map data. As connected residuals in a polymer, neighboring genomic loci have intrinsic mutual dependencies in building a 3D conformation. However, current methods seldom take this feature into account.
Results
We present a method called ShNeigh, which combines the classical MDS technique with local dependence of neighboring loci modeled by a Gaussian formula, to infer the best 3D structure from noisy and incomplete contact frequency matrices. We validated ShNeigh by comparing it to two typical distance-based algorithms, ShRec3D and ChromSDE. The comparison results on simulated Hi-C dataset showed that, while keeping the high-speed nature of classical MDS, ShNeigh can recover the true structure better than ShRec3D and ChromSDE. Meanwhile, ShNeigh is more robust to data noise. On the publicly available human GM06990 Hi-C data, we demonstrated that the structures reconstructed by ShNeigh are more reproducible between different restriction enzymes than by ShRec3D and ChromSDE, especially at high resolutions manifested by sparse contact maps, which means ShNeigh is more robust to signal coverage.
Conclusions
Our method can recover stable structures in high noise and sparse signal settings. It can also reconstruct similar structures from Hi-C data obtained using different restriction enzymes. Therefore, our method provides a new direction for enhancing the reconstruction quality of chromatin 3D structures.
Journal Article
Dynamical control of quantum heat engines using exceptional points
A quantum thermal machine is an open quantum system coupled to hot and cold thermal baths. Thus, its dynamics can be well understood using the concepts and tools from non-Hermitian quantum systems. A hallmark of non-Hermiticity is the existence of exceptional points where the eigenvalues of a non-Hermitian Hamiltonian or a Liouvillian superoperator and their associated eigenvectors coalesce. Here, we report the experimental realization of a single-ion heat engine and demonstrate the effect of Liouvillian exceptional points on the dynamics and the performance of a quantum heat engine. Our experiments have revealed that operating the engine in the exact- and broken-phases, separated by a Liouvillian exceptional point, respectively during the isochoric heating and cooling strokes of an Otto cycle produces more work and output power and achieves higher efficiency than executing the Otto cycle completely in the exact phase where the system has an oscillatory dynamics and higher coherence. This result opens interesting possibilities for the control of quantum heat engines and will be of interest to other research areas that are concerned with the role of coherence and exceptional points in quantum processes and in work extraction by thermal machines.
Investigations of quantum thermal machines and Liouvillian exceptional points have rarely crossed each other. Here, the authors realize experimentally a quantum Otto engine using a single trapped ion, and show that crossing a Liouvillian exceptional point during the cycle increases the engine performance.
Journal Article