The pathological hallmark of Alzheimer disease is the senile plaque principally composed tightly aggregated amyloid-beta fibrils (fAbeta), which are thought to be resistant degradation and clearance. In this study, we explored whether proteases capable degrading soluble Abeta (sAbeta) could degrade fAbeta as well. We demonstrate that matrix metalloproteinase-9 (MMP-9) can ability not shared by other sAbeta-degrading enzymes examined, including endothelin-converting enzyme, insulin-degrading...

It has been postulated that the development of amyloid plaques in Alzheimer's disease (AD) may result from an imbalance between generation and clearance amyloid-β peptide (Aβ). Although familial AD appears to be caused by Aβ overproduction, sporadic (the most prevalent form) impairment clearance. Recent evidence suggests several proteases contribute degradation Aβ. Furthermore, astrocytes have recently implicated as a potential cellular mediator degradation. In this study, we examined...

The accumulation of aggregated amyloid-β (Aβ) in amyloid plaques is a neuropathological hallmark Alzheimer's disease (AD). Reactive astrocytes are intimately associated with plaques; however, their role AD pathogenesis unclear. We deleted the genes encoding two intermediate filament proteins required for astrocyte activation—glial fibrillary acid protein (Gfap) and vimentin (Vim)—in transgenic mice expressing mutant human precursor presenilin-1 (APP/PS1). gene deletions increased plaque...

In sporadic Alzheimer's disease (AD), impaired Aβ removal contributes to elevated extracellular levels that drive amyloid plaque pathogenesis. Extracellular proteolysis, export across the blood-brain barrier, and cellular uptake facilitate physiologic clearance. Astrocytes can take up degrade Aβ, but it remains unclear whether this function is insufficient in AD or be enhanced accelerate removal. Additionally, age-related dysfunction of lysosomes, major degradative organelles wherein...

In AD, an imbalance between Aβ production and removal drives elevated brain levels eventual amyloid plaque deposition. APP undergoes nonamyloidogenic processing via α-cleavage at the plasma membrane, amyloidogenic β- γ-cleavage within endosomes to generate Aβ, or lysosomal degradation in neurons. Considering multiple reports implicating impaired lysosome function as a driver of increased APP, we explored efficacy targeting transcription factor EB (TFEB), master regulator pathways, reduce...

Amyloid plaques are primarily composed of extracellular aggregates amyloid-β (Aβ) peptide and a pathological signature Alzheimer's disease. However, the factors that influence dynamics amyloid plaque formation growth in vivo largely unknown. Using serial intravital multiphoton microscopy through thinned-skull cranial window APP/PS1 transgenic mice, we found appear grow over period weeks before reaching mature size. Growth was more prominent early after initial formation: grew faster...

One of the pathological hallmarks Alzheimer disease is accumulation amyloid plaques in extracellular space brain. Amyloid are primarily composed aggregated β peptide (Aβ), a proteolytic fragment transmembrane precursor protein (APP). For APP to be proteolytically cleaved into Aβ, it must internalized cell and trafficked endosomes where specific protease complexes can cleave APP. Several recent genome-wide association studies have reported that several single nucleotide polymorphisms (SNPs)...

Microglia, the parenchymal tissue macrophages in brain, surround amyloid plaques brains of individuals with Alzheimer's disease (AD) but are ineffective at clearing to mitigate progression. Recent studies mice indicate that microglia derived exclusively from primitive yolk sac hematopoiesis and self-renew without contribution ontogenically distinct monocytes/macrophages definitive adult hematopoietic origin. Using a genetic fate-mapping approach label cells origin throughout life span, we...

Substantial evidence suggests a role for immunotherapy in treating Alzheimer's disease (AD). While the precise pathophysiology of AD is incompletely understood, clinical trials antibodies targeting aggregated forms β amyloid (Aβ) have shown that reducing plaques can mitigate cognitive decline patients with early-stage AD. Here, we describe what believe to be novel approach target and degrade by genetically engineering macrophages express an Aβ-targeting chimeric antigen receptor (CAR-Ms)....

Alzheimer's disease (AD) is characterized by neuronal loss and astrocytosis in the cerebral cortex. However, specific effects that pathological mutations coding variants associated with AD have on cellular composition of brain are often ignored. We developed optimized a cell-type-specific expression reference panel employed digital deconvolution methods to determine distribution three independent transcriptomic studies. found astrocyte relative proportions differ between healthy diseased...

Methylprednisolone (MP) is used to treat a variety of neurological disorders involving white matter injury, including multiple sclerosis, acute disseminated encephalomyelitis, and spinal cord injury (SCI). Although its mechanism action has been attributed anti-inflammatory or antioxidant properties, we examined the possibility that MP may have direct neuroprotective activities. Neurons oligodendrocytes treated with AMPA staurosporine died within 24 h after treatment. attenuated...

Lysosomes are at the epicenter of cellular processes critical for inflammasome activation in macrophages. Inflammasome and IL-1β secretion implicated myocardial infarction (MI) resultant heart failure; however, little is known about how macrophage lysosomes regulate these processes. In mice subjected to cardiac ischemia/reperfusion (IR) injury humans with ischemic cardiomyopathy, we observed evidence lysosomal impairment Inducible macrophage-specific overexpression transcription factor EB...

CD2-associated protein (CD2AP) is an SH3-containing scaffold adaptor which regulates the actin cytoskeleton. Recently, CD2AP was identified as a genetic risk factor for Alzheimer's disease (AD) by several genome-wide association studies. One of hallmarks AD accumulation aggregated forms Amyloid-β (Aβ) in brain. In humans, susceptibility locus (rs9349407) associated with increased plaque burden. Aβ production highly regulated endocytosis and influenced lysosomal function. Lysosomal...

Understanding circuit-level manipulations that affect the brain's capacity for plasticity will inform design of targeted interventions enhance recovery after stroke. Following stroke, increased contralesional activity (e.g. use unaffected limb) can negatively influence recovery, but it is unknown which specific neural connections exert this influence, and to what extent affects systems- molecular-level biomarkers recovery. Here, we combine optogenetic photostimulation with optical intrinsic...

Cerebral amyloid angiopathy (CAA) is a common cause of recurrent intracerebral hemorrhage in the elderly. Previous studies have shown that CAA induces inflammation and expression matrix metalloproteinase-2 metalloproteinase-9 (gelatinases) amyloid-laden vessels. Here, we inhibited both using minocycline mouse models to determine whether spontaneous could be reduced.Tg2576 (n=16) 5xFAD/ApoE4 knockin mice (n=16), aged 17 12 months, respectively, were treated with (50 mg/kg, IP) or saline every...

Methylprednisolone (MP), a synthetic glucocorticoid agonist, is widely used for the clinical therapy of white matter diseases in nervous system, such as spinal cord injury and multiple sclerosis. In addition to its potent anti-inflammatory antioxidant properties, we recently discovered selective antiapoptotic effect MP on oligodendrocytes via activation receptor (GR) upregulation bcl-X L , splicing isoform bcl-x gene. Based published findings functional interactions between GR STAT5,...

VEGI (vascular endothelial growth inhibitor), a member of the tumour necrosis factor superfamily, has been reported to inhibit cell proliferation, angiogenesis and growth. We identified cloned approx. 2.2 kb promoter from mouse cerebral cells. The contained an atypical TATA-box-binding protein sequence TAAAAAA residing at −32/−26 relative transcription initiation site (+1), 83 bp upstream ATG start codon. To investigate critical sequences in promoter, series deleted truncated segments were...

The bcl-x gene appears to play a critical role in regulating apoptosis the developing and mature CNS following injury. Two isoforms of Bcl-x are produced as result alternative pre-mRNA splicing: L (the long form) is anti-apoptotic, while S (short pro-apoptotic. Despite antagonistic activities these two isoforms, little known about how regulation splicing may mediate neural cell apoptosis. Here, we report that apoptotic stimuli (staurosporine or C2-ceramide) reciprocally altered cells,...

Abstract Substantial evidence suggests a role for immunotherapy in treating Alzheimer’s disease (AD). Several monoclonal antibodies targeting aggregated forms of beta amyloid (Aβ), have been shown to reduce plaques and some cases, mitigate cognitive decline early-stage AD patients. We sought determine if genetically engineered macrophages could improve the degradation plaques. Chimeric antigen receptor (CAR-Ms), which show promise as cancer treatment, are an appealing strategy enhance target...

Brains that are affected by Alzheimer’s disease (AD) characterized the overload of extracellular amyloid β (Aβ) peptides, but recent data from cellular and animal models propose Aβ deposition is preceded intraneuronal accumulation direct precursor Aβ, C99. These studies indicate C99 firstly occurs within endosomal lysosomal compartments it contributes to early-stage AD-related endosomal-lysosomal-autophagic defects. Our previous work also suggests itself could be a consequence defective...

Via a transient expression assay system, an experimental study was undertaken to characterize the effects of insect ecdysone and juvenile hormone analogue on luciferase gene under control immediate-early (ie-1) promoter Bombyx mori nuclear polyhedrosis virus. The results demonstrated that transcriptional activity ie-1 increased certain extent by different treatments in uninfected cells or fifth instar silkworm larvae transfected with plasmid containing driven promoter. By treatment alone,...

Abstract Alzheimer’s disease (AD) is characterized by neuronal loss and astrocytosis in the cerebral cortex. However, effects of brain cellular composition are often ignored high-throughput molecular studies. We developed optimized a cell-type specific expression reference panel employed digital deconvolution methods to determine distribution three independent transcriptomic found that astrocyte proportions differ between healthy diseased brains also among AD cases carry genetic risk...

Amyloid plaques and associated reactive gliosis are hallmark pathological features of Alzheimer's disease (AD). Activated microglia believed to be play a role in the direct phagocytosis (albeit impaired) amyloid, suppressing plaque progression; however, precise activated astrocytes is not well-defined. To examine astrocytosis AD, we deleted genes two intermediate filaments required for astrocyte activation-glial fibrillary acid protein (GFAP) vimentin (Vim)-in APP/PS1 mice. Previous studies...