Senolytic and senomorphic secondary metabolites as therapeutic agents in models of Parkinson's disease.

is a valuable model organism for a wide range of biological exploration. The well-known advantages of include its relatively simple biology, the ease with which it is genetically modified, the relatively low financial and time costs associated with their short gestation and life cycles, and the large number of offspring they produce per generation. has facilitated the discovery of many significant insights into the pathology of Parkinson's disease (PD) and has served as an excellent preclinical model of PD-related therapeutic discovery.

Neuroglial Senescence, α-Synucleinopathy, and the Therapeutic Potential of Senolytics in Parkinson's Disease.

Parkinson's disease (PD) is the most common movement disorder and the second most prevalent neurodegenerative disease after Alzheimer's disease. Despite decades of research, there is still no cure for PD and the complicated intricacies of the pathology are still being worked out. Much of the research on PD has focused on neurons, since the disease is characterized by neurodegeneration.

Novel Genetic Signatures Associated With Sporadic Amyotrophic Lateral Sclerosis.

Amyotrophic Lateral Sclerosis (ALS) is a complex polygenetic neurodegenerative disorder. Establishing a diagnosis for ALS is a challenging and lengthy process. By the time a diagnosis is made, the lifespan prognosis is only about two to 5 years.

Deep Convolutional Neural Networks With Ensemble Learning and Generative Adversarial Networks for Alzheimer's Disease Image Data Classification.

Recent advancements in deep learning (DL) have made possible new methodologies for analyzing massive datasets with intriguing implications in healthcare. Convolutional neural networks (CNN), which have proven to be successful supervised algorithms for classifying imaging data, are of particular interest in the neuroscience community for their utility in the classification of Alzheimer's disease (AD). AD is the leading cause of dementia in the aging population.

Upregulation of Alzheimer's Disease Amyloid-β Protein Precursor in Astrocytes Both in vitro and in vivo.

Background: The amyloid cascade hypothesis of Alzheimer's disease (AD) posits that amyloid-β (Aβ) protein accumulation underlies the pathogenesis of the disease by leading to the formation of amyloid plaques, a pathologic hallmark of AD. Aβ is a proteolytic product of amyloid-β protein precursor (AβPP; APP), which is expressed in both neurons and astrocytes. Although considerable evidence shows that astrocytes may play critical roles in the pathogenesis of AD, the longitudinal changes of amyloid plaques in relationship to AβPP expression in astrocytes and cellular consequences are largely unknown.

Molecularly defined cortical astroglia subpopulation modulates neurons via secretion of Norrin.

Despite expanding knowledge regarding the role of astroglia in regulating neuronal function, little is known about regional or functional subgroups of brain astroglia and how they may interact with neurons. We use an astroglia-specific promoter fragment in transgenic mice to identify an anatomically defined subset of adult gray matter astroglia. Using transcriptomic and histological analyses, we generate a combinatorial profile for the in vivo identification and characterization of this astroglia subpopulation.

Astrocyte Heterogeneity in the Adult Central Nervous System.

Astrocytes are the most abundant cell type in the central nervous system (CNS), providing critical roles in the overall maintenance and homeostasis. Over 100 years ago, Cajal first showed morphological depictions of different astrocyte populations. Surprisingly, to date astrocytes remain classified in two groups based on their morphological and neuroanatomical positioning.

Cortical astroglia undergo transcriptomic dysregulation in the G93A SOD1 ALS mouse model.

Astroglia are the most abundant glia cell in the central nervous system, playing essential roles in maintaining homeostasis. Key functions of astroglia include, but are not limited to, neurotransmitter recycling, ion buffering, immune modulation, neurotrophin secretion, neuronal synaptogenesis and elimination, and blood-brain barrier maintenance. In neurological diseases, it is well appreciated that astroglia play crucial roles in the disease pathogenesis.

Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer's mouse model.

Adult hippocampal neurogenesis (AHN) is impaired before the onset of Alzheimer's disease (AD) pathology. We found that exercise provided cognitive benefit to 5×FAD mice, a mouse model of AD, by inducing AHN and elevating levels of brain-derived neurotrophic factor (BDNF). Neither stimulation of AHN alone, nor exercise, in the absence of increased AHN, ameliorated cognition.

Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer's Disease.

Tau is the major constituent of neurofibrillary tangles in Alzheimer's disease (AD), but the mechanism underlying tau-associated neural damage remains unclear. Here, we show that tau can directly interact with nucleoporins of the nuclear pore complex (NPC) and affect their structural and functional integrity. Pathological tau impairs nuclear import and export in tau-overexpressing transgenic mice and in human AD brain tissue.

Soluble Gamma-secretase Modulators Attenuate Alzheimer's β-amyloid Pathology and Induce Conformational Changes in Presenilin 1.

A central pathogenic event of Alzheimer's disease (AD) is the accumulation of the Aβ42 peptide, which is generated from amyloid-β precursor protein (APP) via cleavages by β- and γ-secretase. We have developed a class of soluble 2-aminothiazole γ-secretase modulators (SGSMs) that preferentially decreases Aβ42 levels. However, the effects of SGSMs in AD animals and cells expressing familial AD mutations, as well as the mechanism of γ-secretase modulation remain largely unknown.

3D Printer Generated Tissue iMolds for Cleared Tissue Using Single- and Multi-Photon Microscopy for Deep Tissue Evaluation.

Background: Pathological analyses and methodology has recently undergone a dramatic revolution. With the creation of tissue clearing methods such as CLARITY and CUBIC, groups can now achieve complete transparency in tissue samples in nano-porous hydrogels. Cleared tissue is then imagined in a semi-aqueous medium that matches the refractive index of the objective being used.

Astroglial transcriptome dysregulation in early disease of an ALS mutant SOD1 mouse model.

Astroglia are a morphologically diverse and highly abundant cell type in the CNS. Despite these obvious observations, astroglia still remain largely uncharacterized at the cellular and molecular level. In disease contexts such as amyotrophic lateral sclerosis (ALS), it has been widely shown that astroglia downregulate crucial physiological functions, become hypertrophied, reactive, and toxic to motor neurons.

Astroglia in Thick Tissue with Super Resolution and Cellular Reconstruction.

We utilized the recently published method of passive CLARITY to explore brain astrocytes for the first time with our optimized method. Astrocytes are the fundamental cells in the brain that act to maintain the synaptic activity of neurons, support metabolism of all neurons, and communicate through extensive networks throughout the CNS. They are the defining cell that differentiates lower organisms from humans.

The C9orf72 repeat expansion disrupts nucleocytoplasmic transport.

The hexanucleotide repeat expansion (HRE) GGGGCC (G4C2) in C9orf72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent studies support an HRE RNA gain-of-function mechanism of neurotoxicity, and we previously identified protein interactors for the G4C2 RNA including RanGAP1. A candidate-based genetic screen in Drosophila expressing 30 G4C2 repeats identified RanGAP (Drosophila orthologue of human RanGAP1), a key regulator of nucleocytoplasmic transport, as a potent suppressor of neurodegeneration.