Receptor for advanced glycation endproduct modulators: a new therapeutic target in Alzheimer’s disease

Introduction: Reduction in the deposition of amyloid β (Aβ) has been the primary target for Alzheimer’s disease (AD) therapeutics recently, but in clinical trials this approach has generally been unsuccessful. A common feature of AD pathology is a complex inflammatory component that could be a target for treatment. One feature of this inflammation has been the involvement of the receptor for advanced glycation endproducts (RAGE), whose ligands include advanced glycation-endproduct-modified proteins as well as lipids and Aβ, which are found at elevated levels in AD brains.

Areas covered: In this article, the authors describe the key features of RAGE and how it could have a role in AD pathogenesis. They also summarize experimental animal and clinical data that demonstrate the therapeutic effect of RAGE inhibition and consider what these findings mean for human disease.

Expert opinion: RAGE has multiple ligands, including Aβ, that are increased in AD brains. Inhibiting RAGE-ligand interactions without activating receptor signaling can reduce multiple pathological pathways relevant for AD. Several RAGE inhibitors and modulators are now being tested as therapeutics for AD. Recent Phase II studies have established the good safety and tolerability of TTP448 with some evidence of positive benefit at lower dose. This suggests that further studies are required.     

Novel de novo heterozygous loss-of-function variants in MED13L and further delineation of the MED13L haploinsufficiency syndrome

MED13L haploinsufficiency has recently been described as responsible for syndromic intellectual disability. We planned a search for causative gene variants in seven subjects with intellectual disability and overlapping dysmorphic facial features such as bulbous nasal tip, short mouth and straight eyebrows. We found two de novo frameshift variants in MED13L, consisting in single-nucleotide deletion (c.3765delC) and duplication (c.607dupT). A de novo nonsense variant (c.4420A>T) in MED13L was detected in a further subject in the course of routine whole-exome sequencing. By analyzing the clinical data of our patients along with those recently described in the literature, we confirm that there is a common, recognizable phenotype associated with MED13L haploinsufficiency, which includes intellectual disability and a distinctive facial appearance. Congenital heart diseases are found in some subjects with various degree of severity. Our observation of cleft palate, ataxia, epilepsy and childhood leukemia observed in single cases broadens the known clinical spectrum. Haploinsufficiency for MED13L should be considered in the differential diagnosis of the 1p36 microdeletion syndrome, due to overlapping dysmorphic facial features in some patients. The introduction of massive parallel-sequencing techniques into clinical practice is expected to allow for detection of other causative point variants in MED13L. Analysis of genomic data in connection with deep clinical evaluation of patients could elucidate genetic heterogeneity of the MED13L haploinsufficiency phenotype.     

Differential processing of amyloid precursor protein in brain and in peripheral blood leukocytes

Because amyloid precursor protein (APP) fragments exist in many tissues throughout the body, including the fluid compartments of blood, they have been the focus of numerous investigations into their potential as a biomarker of Alzheimer's disease. Using immunohistochemistry, immunoelectron microscopy, Western blot, and quantitative real-time-polymerase chain reaction (qRT-PCR) analysis we examined whether APP processing in leukocytes is analogous to APP processing in the brain. We show APP immunoreactivity at light and electron microscopic levels in the cytoplasm and nucleus of peripheral blood leukocytes (PBL) yet our Western blot analysis data demonstrated that brain and PBL contain different APP fragments and differentially expressed APP processing enzymes. A Disintegrin and Metalloproteinase domain 10 (ADAM10), nicastrin, and beta-secretase 2 (BACE2) were present in brain but were undetected in PBL. Presenilin 1 and beta-secretase 1 (BACE1) were detected in both tissues but showed different patterns in Western blots. Quantitative PCR results identified Neprilysin as the only processing enzyme we interrogated in which Western and quantitative PCR data coincided. Although our data on differential processing of APP in brain and PBL point to exercising caution when generalizing between blood and brain with regard to mechanisms, they have no implications regarding utility as biomarkers.     

The Influence of Deep Brain Stimulation Intensity and Duration on Symptoms Evolution in an OFF Stimulation Dystonia Study

BackgroundDeep brain stimulation (DBS) of the internal globus pallidus (GPi) is an established therapy for primary generalized dystonia. However, the evolution of dystonia symptoms after DBS discontinuation after years of therapy has only rarely been reported. We therefore longitudinally studied the main physiological measurements known to be impaired in dystonia, with DBS ON and then again after termination of DBS, after at least five years of continuous DBS.ObjectiveWe studied whether dystonia evolution after DBS discontinuation in patients benefiting from long-term GPi DBS is different from that observed in earlier stages of the therapy.MethodsIn eleven DYT1 patients treated with bilateral GPi DBS for at least 5 years, dystonia was assessed ON-DBS, immediately after switch-off (OFF-DBS1) and 48 h after DBS termination (OFF-DBS2). We studied the influence of DBS intensity on dystonia when DBS was discontinued.ResultsOn average a significant difference in symptoms was measured only between ON-DBS and OFF-DBS1 conditions. Importantly, none of the patients returned to their preoperative dystonia severity, even 48 h after discontinuation. The amount of clinical deterioration in the OFF conditions positively correlated with higher stimulation current in the chronic ON-DBS condition.ConclusionsThe duration of DBS application influences symptom evolution after DBS termination. DBS intensity seems to have a prominent role on evolution of dystonic symptoms when DBS is discontinued. In conclusion, DBS induces changing modulation of the motor network with less worsening of symptoms after long term stimulation, when DBS is stopped.