Michael T. Heneka

NLRP3 is activated in Alzheimer´s disease and contributes to pathology in APP/PS1 mice

Alzheimer’s disease is the world’s most common dementing illness. Deposition of amyloid-β peptide drives cerebral neuroinflammation by activating microglia. Indeed, amyloid-β activation of the NLRP3 inflammasome in microglia is fundamental for interleukin-1β maturation and subsequent inflammatory events. However, it remains unknown whether NLRP3 activation contributes to Alzheimer’s disease in vivo. Here we demonstrate strongly enhanced active caspase-1 expression in human mild cognitive impairment and brains with Alzheimer’s disease, suggesting a role for the inflammasome in this neurodegenerative disease. Nlrp3−/− or Casp1−/− mice carrying mutations associated with familial Alzheimer’s disease were largely protected from loss of spatial memory and other sequelae associated with Alzheimer’s disease, and demonstrated reduced brain caspase-1 and interleukin-1β activation as well as enhanced amyloid-β clearance. Furthermore, NLRP3 inflammasome deficiency skewed microglial cells to an M2 phenotype and resulted in the decreased deposition of amyloid-β in the APP/PS1 model of Alzheimer’s disease. These results show an important role for the NLRP3/caspase-1 axis in the pathogenesis of Alzheimer’s disease, and suggest that NLRP3 inflammasome inhibition represents a new therapeutic intervention for the disease.

Antineoplastic effects of peroxisome proliferatoractivated receptor γ agonists

Summary Peroxisome proliferator-activated receptors (PPAR) are members of a superfamily of nuclear hormone receptors. Activation of PPAR isoforms elicits both antineoplastic and anti-inflammatory effects in several types of mammalian cells. PPARs are ligand-activated transcription factors and have a subfamily of three different isoforms: PPARα, PPARγ, and PPARβ/δ. All isoforms heterodimerise with the 9-cisretinoic acid receptor RXR, and play an important part in the regulation of several metabolic pathways, including lipid biosynthesis and glucose metabolism. Endogenous ligands of PPARγ include long-chain polyunsaturated fatty acids, eicosanoid derivates, and oxidised lipids. Newly developed synthetic ligands include thiazolidinediones—a group of potent PPARγ agonists and antidiabetic agents. Here, we review PPARγ-induced antineoplastic signalling pathways, and summarise the antineoplastic effects of PPARγ agonists in different cancer cell lines, animal models, and clinical trials.

Innate immune activation in neurodegenerative disease

The triggering of innate immune mechanisms is emerging as a crucial component of major neurodegenerative diseases. Microglia and other cell types in the brain can be activated in response to misfolded proteins or aberrantly localized nucleic acids. This diverts microglia from their physiological and beneficial functions, and leads to their sustained release of pro-inflammatory mediators. In this Review, we discuss how the activation of innate immune signalling pathways — in particular, the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome — by aberrant host proteins may be a common step in the development of diverse neurodegenerative disorders. During chronic activation of microglia, the sustained exposure of neurons to pro-inflammatory mediators can cause neuronal dysfunction and contribute to cell death. As chronic neuroinflammation is observed at relatively early stages of neurodegenerative disease, targeting the mechanisms that drive this process may be useful for diagnostic and therapeutic purposes.

Glial cells in (patho)physiology.

J. Neurochem. (2012) 121, 4–27.

Neuroinflammatory processes in Alzheimer’s disease

Generation of neurotoxic amyloid β peptides and their deposition along with neurofibrillary tangle formation represent key pathological hallmarks in Alzheimer’s disease (AD). Recent evidence suggests that inflammation may be a third important component which, once initiated in response to neurodegeneration or dysfunction, may actively contribute to disease progression and chronicity. Various neuroinflammatory mediators including complement activators and inhibitors, chemokines, cytokines, radical oxygen species and inflammatory enzyme systems are expressed and released by microglia, astrocytes and neurons in the AD brain. Degeneration of aminergic brain stem nuclei including the locus ceruleus and the nucleus basalis of Meynert may facilitate the occurrence of inflammation in their projection areas given the antiinflammatory and neuroprotective action of their key transmitters norepinephrine and acetylcholine. While inflammation has been thought to arise secondary to degeneration, recent experiments demonstrated that inflammatory mediators may stimulate amyloid precursor protein processing by various means and therefore can establish a vicious cycle. Despite the fact that some aspects of inflammation may even be protective for bystander neurons, antiinflammatory treatment strategies should therefore be considered. Non-steroidal anti-inflammatory drugs have been shown to reduce the risk and delay the onset to develop AD. While, the precise molecular mechanism underlying this effect is still unknown, a number of possible mechanisms including cyclooxygenase 2 or γ-secretase inhibition and activation of the peroxisome proliferator activated receptor γ may alone or, more likely, in concert account for the epidemiologically observed protection.

Protective action of the peroxisome proliferator-activated receptor-γ agonist pioglitazone in a mouse model of Parkinson's disease

We examined the effect of pioglitazone, a peroxisome proliferator‐activated receptor‐γ (PPARγ)agonistofthethiazolidinedione class, on dopaminergic nerve cell death and glial activation in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse model of Parkinsons disease. The acute intoxication of C57BL/6 mice with MPTP led to nigrostriatal injury, as determined by tyrosine hydroxylase (TH) immunocytochemistry, and HPLC detection of striatal dopamine and metabolites. Damage to the nigrostriatal dopamine system was accompanied by a transient activation of microglia, as determined by macrophage antigen‐1 (Mac‐1) and inducible nitric oxide synthase (iNOS) immunoreactivity, and a prolonged astrocytic response. Orally administered pioglitazone (∼ 20 mg/kg/day) attenuated the MPTP‐inducedglialactivation and prevented the dopaminergic cell loss in the substantia nigra pars compacta (SNpc). In contrast, there was little reduction of MPTP‐induced dopamine depletion, with no detectable effect on loss of TH immunoreactivity and glial response in the striatum of pioglitazone‐treated animals. Low levels of PPARγ expression were detected in the ventral mesencephalon and striatum, and were unaffected by MPTP or pioglitazone treatment. Since pioglitazone affects primarily the SNpc in our model, different PPARγ‐independent mechanisms may regulate glial activation in the dopaminergic terminals compared with the dopaminergic cell bodies after acute MPTP intoxication.

Protection by pioglitazone in the MPTP model of Parkinson's disease correlates with IκBα induction and block of NFκB and iNOS activation

Inflammation has been implicated in the pathogenesis of Parkinsons disease (PD). In the chronic 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) model of PD, inducible NO synthase (iNOS) derived nitric oxide (NO) is an important mediator of dopaminergic cell death. Ligands of the peroxisome proliferator‐activated receptor (PPAR) exert anti‐inflammatory effects. We here investigated whether pioglitazone, a PPARγ agonist, protected mice from MPTP‐induced dopaminergic cell loss, glial activation, and loss of catecholamines in the striatum. As shown by western blot, PPARγ was expressed in the striatum and the substantia nigra of vehicle‐ and MPTP‐treated mice. Oral administration of 20 mg/(kg day) of pioglitazone protected tyrosine hydroxylase (TH)‐positive substantia nigra neurons from death induced by 5 × 30 mg/kg MPTP. However, the decrease of dopamine in the striatum was only partially prevented. In mice treated with pioglitazone, there were a reduced activation of microglia, reduced induction of iNOS‐positive cells and less glial fibrillary acidic protein positive cells in both striatum and substantia nigra pars compacta. In addition, treatment with pioglitazone almost completely blocked staining of TH‐positive neurons for nitrotyrosine, a marker of NO‐mediated cell damage. Because an increase in inhibitory protein‐κ‐Bα (IκBα) expression and inhibition of translocation of the nuclear factor kappaB (NFκB) subunit p65 to the nucleus in dopaminergic neurons, glial cells and astrocytes correlated with the protective effects of pioglitazone, our results suggest that pioglitazone sequentially acts through PPARγ activation, IκBα induction, block of NFκB activation, iNOS induction and NO‐mediated toxicity. In conclusion, treatment with pioglitazone may offer a treatment opportunity in PD to slow the progression of disease that is mediated by inflammation.

Peroxisome proliferator-activated receptor-γ agonists prevent experimental autoimmune encephalomyelitis

The development of clinical symptoms in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) involves T‐cell activation and migration into the central nervous system, production of glial‐derived inflammatory molecules, and demyelination and axonal damage. Ligands of the peroxisome proliferator‐activated receptor (PPAR) exert anti‐inflammatory effects on glial cells, reduce proliferation and activation of T cells, and induce myelin gene expression. We demonstrate in two models of EAE that orally administered PPARγ ligand pioglitazone reduced the incidence and severity of monophasic, chronic disease in C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein peptide and of relapsing disease in B10.Pl mice immunized with myelin basic protein. Pioglitazone also reduced clinical signs when it was provided after disease onset. Clinical symptoms were reduced by two other PPARγ agonists, suggesting a role for PPARγ activation in protective effects. The suppression of clinical signs was paralleled by decreased lymphocyte infiltration, lessened demyelination, reduced chemokine and cytokine expression, and increased inhibitor of kappa B (IkB) expression in the brain. Pioglitazone also reduced the antigen‐dependent interferon‐γ production from EAE‐derived T cells. These results suggest that orally administered PPARγ agonists could provide therapeutic benefit in demyelinating disease.

Contribution of inflammatory processes to Alzheimer's disease: molecular mechanisms

There is compelling evidence that Alzheimers disease (AD) amyloid‐β (Aβ) deposition is associated with a local inflammatory response, which is initiated by the activation of microglia and the recruitment of astrocytes. These cells secrete a number of cytokines and neurotoxic products that may contribute to neuronal degeneration and cell death. It has been documented that long‐term intake of non‐steroidal anti‐inflammatory drugs (NSAIDs) decrease the risk for developing AD and delay the onset of the disease. The mechanism behind these NSAIDs is still controversial and several hypotheses have been raised, including changes in the amyloid precursor protein (APP) metabolism, in Aβ aggregation and a decrease in inflammatory mediators. Recently, it was proposed that some NSAIDs might activate the peroxisome proliferator‐activated receptor‐γ (PPAR‐γ). PPAR‐γ belongs to a family of nuclear receptors that are able to regulate the transcription of pro‐inflammatory molecules, such as iNOS. The activation of PPAR‐γ has been recently reported to reduce Aβ levels in cell culture and AD animal models. The implication of PPAR‐γ in the control of Aβ‐induced inflammation suggests a new target for AD therapy and emphasize the contribution of neuroinflammatory mechanisms to the pathogenesis of AD.

The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers.

The cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)‐42, total‐tau (T‐tau), and phosphorylated‐tau (P‐tau) demonstrate good diagnostic accuracy for Alzheimers disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimers Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch‐to‐batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program.