Therapeutic potential of Nlrp1 inflammasome, Caspase-1, or Caspase-6 against Alzheimer disease cognitive impairment.

The sequential activation of Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing protein 1 (Nlrp1) inflammasome, Caspase-1 (Casp1), and Caspase-6 (Casp6) is implicated in primary human neuron cultures and Alzheimer Disease (AD) neurodegeneration. To validate the Nlrp1-Casp1-Casp6 pathway in vivo, the APP J20 AD transgenic mouse model was generated on either a Nlrp1, Casp1 or Casp6 null genetic background and mice were studied at 4-5 months of age. Episodic memory deficits assessed with novel object recognition were normalized by genetic ablation of Nlrp1, Casp1, or Casp6 in J20 mice.

Caspase-6-cleaved Tau fails to induce Tau hyperphosphorylation and aggregation, neurodegeneration, glial inflammation, and cognitive deficits.

Active Caspase-6 (Casp6) and Tau cleaved by Casp6 at amino acids 402 (Tau∆D402) and 421 (Tau∆D421) are present in early Alzheimer disease intraneuronal neurofibrillary tangles, which are made primarily of filamentous Tau aggregates. To assess whether Casp6 cleavage of Tau contributes to Tau pathology and Casp6-mediated age-dependent cognitive impairment, we generated transgenic knock-in mouse models that conditionally express full-length human Tau (hTau) 0N4R only (CTO) or together with human Casp6 (hCasp6) (CTC). Region-specific hippocampal and cortical hCasp6 and hTau expression were confirmed with western blot and immunohistochemistry in 2-25-month-old brains.

Pre-symptomatic Caspase-1 inhibitor delays cognitive decline in a mouse model of Alzheimer disease and aging.

Early therapeutic interventions are essential to prevent Alzheimer Disease (AD). The association of several inflammation-related genetic markers with AD and the early activation of pro-inflammatory pathways in AD suggest inflammation as a plausible therapeutic target. Inflammatory Caspase-1 has a significant impact on AD-like pathophysiology and Caspase-1 inhibitor, VX-765, reverses cognitive deficits in AD mouse models.

Methylene blue inhibits Caspase-6 activity, and reverses Caspase-6-induced cognitive impairment and neuroinflammation in aged mice.

Activated Caspase-6 (Casp6) is associated with age-dependent cognitive impairment and Alzheimer disease (AD). Mice expressing human Caspase-6 in hippocampal CA1 neurons develop age-dependent cognitive deficits, neurodegeneration and neuroinflammation. This study assessed if methylene blue (MB), a phenothiazine that inhibits caspases, alters Caspase-6-induced neurodegeneration and cognitive impairment in mice.

Caspase-1 inhibition alleviates cognitive impairment and neuropathology in an Alzheimer's disease mouse model.

Alzheimer's disease (AD) is an intractable progressive neurodegenerative disease characterized by cognitive decline and dementia. An inflammatory neurodegenerative pathway, involving Caspase-1 activation, is associated with human age-dependent cognitive impairment and several classical AD brain pathologies. Here, we show that the nontoxic and blood-brain barrier permeable small molecule Caspase-1 inhibitor VX-765 dose-dependently reverses episodic and spatial memory impairment, and hyperactivity in the J20 mouse model of AD.

Differential susceptibility of striatal, hippocampal and cortical neurons to Caspase-6.

Active cysteinyl protease Caspase-6 is associated with early Alzheimer and Huntington diseases. Higher entorhinal cortex and hippocampal Caspase-6 levels correlate with lower cognitive performance in aged humans. Caspase-6 induces axonal degeneration in human primary neuron cultures and causes inflammation and neurodegeneration in mouse hippocampus, and age-dependent memory impairment.

Ganglioside and related-sphingolipid profiles are altered in a cellular model of Alzheimer's disease.

Sphingolipid-related issues are increasingly discussed to contribute to the neuropathological process of Alzheimer's disease (AD). In this study, gangliosides and related-sphingolipids (ceramides, neutral glycosphingolipids and sphingomyelins) were analyzed in neuroglioma (H4) cells expressing the Swedish mutation of the human amyloid precursor protein (H4APPsw) and compared with those of wild-type control H4 cells. These cells were chosen since H4APPsw cells were previously reported to reproduce well some essential features of AD.

Caspase vinyl sulfone small molecule inhibitors prevent axonal degeneration in human neurons and reverse cognitive impairment in Caspase-6-overexpressing mice.

Background: The activation of the aspartate-specific cysteinyl protease, Caspase-6, is proposed as an early pathogenic event of Alzheimer disease (AD) and Huntington's disease. Caspase-6 inhibitors could be useful against these neurodegenerative diseases but most Caspase-6 inhibitors have been exclusively studied in vitro or show acute liver toxicity in humans. Here, we assessed vinyl sulfone small molecule peptide caspase inhibitors for potential use in vivo.

Anti-amyloidogenic effects of glycosphingolipid synthesis inhibitors occur independently of ganglioside alterations.

Evidence has suggested that ganglioside abnormalities may be linked to the proteolytic processing of amyloid precursor protein (APP) in Alzheimer's disease (AD) and that pharmacological inhibition of ganglioside synthesis may reduce amyloid β-peptide (Aβ) production. In this study, we assessed the usefulness of two well-established glycosphingolipid (GSL) synthesis inhibitors, the synthetic ceramide analog D-PDMP (1-phenyl 2-decanoylamino-3-morpholino-1-propanol) and the iminosugar N-butyldeoxynojirimycin (NB-DNJ or miglustat), as anti-amyloidogenic drugs in a human cellular model of AD. We found that both GSL inhibitors were able to markedly inhibit Aβ production, although affecting differently the APP cleavage.

The Tyr216 phosphorylated form of GSK3β contributes to tau phosphorylation at PHF-1 epitope in response to Aβ in the nucleus of SH-SY5Y cells.

Aims: GSK3β activation in Aβ conditions leading to tau phosphorylation at pathological sites is a well-known phenomenon. However, the serine/tyrosine phosphorylation processes implied in Aβ-induced GSK3β activation and responsible for tau phosphorylation, especially at the GSK3β specific Ser396/Ser404 (PHF-1) site, are still debated.

Main Methods: Experiments were performed on SH-SY5Y cells exposed to 20μM Aβ1-42 in a time ranging from 5min to 8h.

Dendritic Spine Loss and Chronic White Matter Inflammation in a Mouse Model of Highly Repetitive Head Trauma.

Mild traumatic brain injury (mTBI) is an emerging risk for chronic behavioral, cognitive, and neurodegenerative conditions. Athletes absorb several hundred mTBIs each year; however, rodent models of repeat mTBI (rmTBI) are often limited to impacts in the single digits. Herein, we describe the effects of 30 rmTBIs, examining structural and pathological changes in mice up to 365 days after injury.

Inhibition of GSK3β by pharmacological modulation of sphingolipid metabolism occurs independently of ganglioside disturbance in a cellular model of Alzheimer's disease.

Accumulating evidence implicates ganglioside and/or related-sphingolipid disturbance in the pathogenesis of Alzheimer's disease (AD). However, it is not known whether these lipidic alterations are connected with other important features of AD, such as deregulated insulin/Akt/GSK3 signaling. In this study, we have treated neuroglioma cells expressing the double Swedish mutation of human amyloid precursor protein (H4APPsw) with several glycosphingolipid (GSL)-modulating agents, and we have analyzed the impact of the aberrant ganglioside composition on the GSK3 activation state.

Dexmedetomidine increases tau phosphorylation under normothermic conditions in vivo and in vitro.

There is developing interest in the potential association between anesthesia and the onset and progression of Alzheimer's disease. Several anesthetics have, thus, been demonstrated to induce tau hyperphosphorylation, an effect mostly mediated by anesthesia-induced hypothermia. Here, we tested the hypothesis that acute normothermic administration of dexmedetomidine (Dex), an intravenous sedative used in intensive care units, would result in tau hyperphosphorylation in vivo and in vitro.

ERK (MAPK) does not phosphorylate tau under physiological conditions in vivo or in vitro.

Alzheimer's disease is characterized by the deposition of intracellular aggregates of hyperphosphorylated tau protein. Tau hyperphosphorylation has been attributed in part to the deregulation of kinases and phosphatases activities. Extracellular signal regulated-kinases 1/2 (ERK1/2) were reported to be activated in the first stages of Alzheimer's disease and were proposed as a potential therapeutic target.

Tau hyperphosphorylation and deregulation of calcineurin in mouse models of Huntington's disease.

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by polyglutamine expansions in the amino-terminal region of the huntingtin (Htt) protein. At the cellular level, neuronal death is accompanied by the proteolytic cleavage, misfolding and aggregation of huntingtin. Abnormal hyperphosphorylation of tau protein is a characteristic feature of a class of neurodegenerative diseases called tauopathies.

Lithium chloride and staurosporine potentiate the accumulation of phosphorylated glycogen synthase kinase 3β/Tyr216, resulting in glycogen synthase kinase 3β activation in SH-SY5Y human neuroblastoma cell lines.

Glycogen synthase kinase 3β (GSK3β) activity is regulated by phosphorylation processes and regulates in turn through phosphorylation several proteins, including eukaryotic initiation factor 2B (eIF2B). Serine 9 phosphorylation of GSK3β (pGSK3βSer9), usually promoted by activation of the PI3K/Akt survival pathway, triggers GSK3β inhibition. By contrast, tyrosine 216 phosphorylation of GSK3β (pGSK3βTyr216) increases under apoptotic conditions, leading to GSK3β activation.

Ceramide and Related-Sphingolipid Levels Are Not Altered in Disease-Associated Brain Regions of APP and APP/PS1 Mouse Models of Alzheimer's Disease: Relationship with the Lack of Neurodegeneration?

There is evidence linking sphingolipid abnormalities, APP processing, and neuronal death in Alzheimer's disease (AD). We previously reported a strong elevation of ceramide levels in the brain of the APP(SL)/PS1Ki mouse model of AD, preceding the neuronal death. To extend these findings, we analyzed ceramide and related-sphingolipid contents in brain from two other mouse models (i.