Profile of gantenerumab and its potential in the treatment of Alzheimer's disease.

Alzheimer's disease, which is characterized by gradual cognitive decline associated with deterioration of daily living activities and behavioral disturbances throughout the course of the disease, is estimated to affect 27 million people around the world. It is expected that the illness will affect about 63 million people by 2030, and 114 million by 2050, worldwide. Current Alzheimer's disease medications may ease symptoms for a time but are not capable of slowing down disease progression. Indeed, all currently available therapies, such as cholinesterase inhibitors (donepezil, galantamine, rivastigmine), are primarily considered symptomatic therapies, although recent data also suggest possible disease-modifying effects. Gantenerumab is an investigational fully human anti-amyloid beta monoclonal antibody with a high capacity to bind and remove beta-amyloid plaques in the brain. This compound, currently undergoing Phase II and III clinical trials represents a promising agent with a disease-modifying potential in Alzheimer's disease. Here, we present an overview of gantenerumab ranging from preclinical studies to human clinical trials.

Calcineurin inhibition rescues early synaptic plasticity deficits in a mouse model of Alzheimer's disease.

Functional and ultrastructural investigations support the concept that altered brain connectivity, exhausted neural plasticity, and synaptic loss are the strongest correlates of cognitive decline in age-related neurodegenerative dementia of Alzheimer's type. We have previously demonstrated that in transgenic mice, expressing amyloid-ß precursor protein-Swedish mutation active caspase-3 accumulates in hippocampal postsynaptic compartments leading to altered postsynaptic density (PSD) composition, increased long-term depression (LTD), and dendritic spine loss. Furthermore, we found strong evidence that dendritic spine alteration is mediated by calcineurin activation, a calcium-dependent phosphatase involved in synapse signaling. In the present work, we analyzed the molecular mechanism linking alteration of synaptic plasticity to the increase of calcineurin activity. We found that acute treatment of young and plaque-free transgenic mice with the calcineurin inhibitor FK506 leads to a complete rescue of LTD and PSD composition. Our findings are in agreement with other results reporting that calcineurin inhibition improves memory function and restores dendritic spine density, confirming that calcineurin inhibition may be explored as a neuroprotective treatment to stop or slowdown synaptic alterations in Alzheimer's disease.

Reelin haploinsufficiency reduces the density of PV+ neurons in circumscribed regions of the striatum and selectively alters striatal-based behaviors.

RATIONALE: Reelin, a large extracellular matrix glycoprotein, is down-regulated in the brain of schizophrenic patients and of heterozygous reeler mice (rl/+). The behavioral phenotype of rl/- mice, however, matches only partially the schizophrenia hallmarks. OBJECTIVES: We recently reported (Marrone et al., Eur J Neurosci 24:20062-22070, 2006) that homozygous reeler mutants (rl/rl) exhibit reduced density of parvalbumin-positive (PV+) GABAergic interneurons in anatomically circumscribed regions of the neostriatum. Assuming that in rl/+ mice may also show regional reduction of striatal GABAergic interneurons, behavioral impairments should selectively emerge in tasks depending on specifically altered striatal circuits. MATERIALS AND METHODS: We mapped the density of striatal PV+ interneurons in rl/+ and wild-type (+/+) mice and measured their performance in tasks depending on distinct striatal subregions. RESULTS: Our findings show that, contrary to what would be expected on the basis of gene dosage criteria, the striatal regions in which rl/rl mice exhibited decreased density of PV+ interneurons were either unaltered (rostral striatum) or equally altered (dorsomedial and ventromedial intermediate striatum, caudal striatum) in rl/+ mice. The anatomical findings were paralleled by behavioral deficits in fear extinction and latent inhibition, respectively, requiring the dorsomedial and ventromedial striatal regions. Conversely, active avoidance performance, which requires the dorsolateral region, was unaffected. CONCLUSIONS: Reelin haploinsufficiency alters the density of PV+ neurons in circumscribed regions of the striatum and selectively disrupts behaviors sensitive to dysfunction of these targeted regions. This aspect should be considered when designing experiments aimed at evaluating the impact of reelin haploinsufficiency in schizophrenia-associated cognitive disturbances in rl/+ mutants.

Protective role of hydrogen peroxide in oxygen-deprived dopaminergic neurones of the rat substantia nigra.

Hydrogen peroxide (H2O2) is a reactive oxygen species, responsible for cytotoxic damage through the formation of hydroxyl radicals. Dopamine (DA) neurones of the substantia nigra pars compacta (SNc) are highly sensitive to metabolic stress, and they typically respond to energy deprivation with membrane hyperpolarization, mainly through opening of ATP-dependent K+ channels. Accordingly, H2O2 (3 mM) induced a tolbutamide-sensitive outward current in DA neurones. Conversely, in a hypoxic medium, H2O2 reverted membrane hyperpolarization, which is associated with oxygen deprivation in DA neurones, restored their action potential firing, and reduced the hypoxia-mediated outward current in a concentration-dependent manner, between 0.1 and 3 mM (IC50 0.6+/-0.1 mM). Notably, H2O2 did not counteract membrane hyperpolarization associated with hypoglycaemia, moreover, when catalase was inhibited with 3-amino-1,2,4-triazole (3-AT; 30 mM), H2O2 did not reduce hypoxia-mediated outward current. The counteracting action of H2O2 on hypoxia-mediated effects was further confirmed by single-unit extracellular recordings of presumed DA neurones in acute midbrain slices preparations, using a planar multi-electrode array device. Whilst a prolonged period of hypoxia (40 min) caused firing suppression, which did not recover after perfusion in normoxic conditions, the presence of H2O2 (3 mM) during this prolonged hypoxic period rescued most of the neurones from irreversible firing inhibition. Accordingly, morphological studies showed that H2O2 counteracts the cytochrome c release provoked by prolonged hypoxic treatment. Taken together, our data suggest that H2O2 prevents the metabolic stress of DA neurones induced by hypoxia by serving as a supplementary source of molecular oxygen, through its degradation by catalase.

Dopamine selectively reduces GABA(B) transmission onto dopaminergic neurones by an unconventional presynaptic action.

The functioning of midbrain dopaminergic neurones is closely involved in mental processes and movement. In particular the modulation of the inhibitory inputs on these cells might be crucial in controlling firing activity and dopamine (DA) release in the brain. Here, we report a concentration-dependent depressant action of dopamine on the GABA(B) IPSPs intracellularly recorded from dopaminergic neurones. Such effect was observed in spite of the presence of D(1)/D(2) dopamine receptor antagonists. A reduction of the GABA(B) IPSPs was also caused by noradrenaline (norepinephrine) and by L-beta-3,4-dihydroxyphenylalanine (L-DOPA), which is metabolically transformed into DA. The DA-induced depression of the IPSPs was partially antagonised by the alpha2 antagonists yohimbine and phentolamine. DA did not change the postsynaptic effects of the GABA(B) agonist baclofen, suggesting a presynaptic site of action. Furthermore, DA did not modulate the GABA(A)-mediated IPSP. The DA-induced depression of the GABA(B) IPSP occluded the depression produced by serotonin and was not antagonized by serotonin antagonists. The DA- and 5-HT-induced depression of the GABA(B) IPSP persisted when calcium and potassium currents were reduced in to the presynaptic terminals. These results describe an unconventional presynaptic, D(1) and D(2) independent action of DA on the GABA(B) IPSP. This might have a principal role in determining therapeutic/side effects of L-DOPA and antipsychotics and could be also involved in drug abuse.