Genetic and pharmacologic enhancement of SUMO2 conjugation prevents and reverses cognitive impairment and synaptotoxicity in a preclinical model of Alzheimer's disease.

Introduction: Amyloid beta oligomers (Aβos) are toxic to synapses and key to the progression of Alzheimer's disease (AD) and amyloid pathology, representing a target for therapeutic strategies.

Methods: Amyloid and small ubiquitin modifier 2 (SUMO2) transgenics were analyzed by electrophysiology and behavioral testing. A recombinant analogue of SUMO2, SBT02, was generated and assessed for brain penetration and the ability to mitigate amyloid pathology.

Bacterial pathogen deploys iminosugar galactosyrin to manipulate plant glycobiology.

The extracellular space (apoplast) of plants is an important molecular battleground during infection by many pathogens. We previously found that a plant-secreted β-galactosidase BGAL1 acts in immunity by facilitating the release of immunogenic peptides from bacterial flagellin and that suppresses this enzyme by producing a small molecule inhibitor called galactosyrin. Here, we elucidated the structure and biosynthesis of galactosyrin and uncovered its multifunctional roles during infection.

Systems-Level Interactome Mapping Reveals Actionable Protein Network Dysregulation Across the Alzheimer's Disease Spectrum.

Alzheimer's disease (AD) progresses as a continuum, from preclinical stages to late-stage cognitive decline, yet the molecular mechanisms driving this progression remain poorly understood. Here, we provide a systems-level map of protein-protein interaction (PPI) network dysfunction across the AD spectrum and uncover epichaperomes-stable scaffolding platforms formed by chaperones and co-factors-as central drivers of this process. Using over 100 human brain specimens, mouse models, and human neurons, we show that epichaperomes emerge early, even in preclinical AD, and progressively disrupt multiple PPI networks critical for synaptic function and neuroplasticity.

Brain microenvironment-remodeling nanomedicine improves cerebral glucose metabolism, mitochondrial activity and synaptic function in a mouse model of Alzheimer's disease.

The development of disease-modifying therapeutics for Alzheimer's disease remains challenging due to the complex pathology and the presence of the blood-brain barrier. Previously we have described the investigation of a brain-penetrating multifunctional bioreactive nanoparticle system capable of remodeling the hypoxic and inflammatory brain microenvironment and reducing beta-amyloid plaques improving cognitive function in a mouse model of Alzheimer's disease. Despite the linkage of hypoxia and inflammation to metabolic alteration, the effects of this system on modulating cerebral glucose metabolism, mitochondrial activity and synaptic function remained to be elucidated.

Enhancing quality and yield of recombinant secretory IgA antibodies in Nicotiana benthamiana by endoplasmic reticulum engineering.

The production of complex multimeric secretory immunoglobulins (SIgA) in Nicotiana benthamiana leaves is challenging, with significant reductions in complete protein assembly and consequently yield, being the most important difficulties. Expanding the physical dimensions of the ER to mimic professional antibody-secreting cells can help to increase yields and promote protein folding and assembly. Here, we expanded the ER in N.