The presenilin 1 mutation P436S causes familial Alzheimer's disease with elevated Aß43 and atypical clinical manifestations.

INTRODUCTION: Familial Alzheimer's disease (fAD) is heterogeneous in terms of age at onset and clinical presentation. A greater understanding of the pathogenicity of fAD variants and how these contribute to heterogeneity will enhance our understanding of the mechanisms of AD more widely. METHODS: To determine the pathogenicity of the unclassified PSEN1 P436S mutation, we studied an expanded kindred of eight affected individuals, with magnetic resonance imaging (MRI) (two individuals), patient-derived induced pluripotent stem cell (iPSC) models (two donors), and post-mortem histology (one donor). RESULTS: An autosomal dominant pattern of inheritance of fAD was seen, with an average age at symptom onset of 46 years and atypical features. iPSC models and post-mortem tissue supported high production of amyloid beta 43 (Aß43). PSEN1 peptide maturation was unimpaired. DISCUSSION: We confirm that the P436S mutation in PSEN1 causes atypical fAD. The location of the mutation in the critical PSEN1 proline-alanine-leucine-proline (PALP) motif may explain the early age at onset despite appropriate protein maturation. HIGHLIGHTS: PSEN1 P436S mutations cause familial Alzheimer's disease. This mutation is associated with atypical clinical presentation. Induced pluripotent stem cells (iPSCs) and post-mortem studies support increased amyloid beta (Aß43) production. Early age at onset highlights the importance of the PALP motif in PSEN1 function.

C9orf72 hexanucleotide repeat expansion found in suspected spinobulbar muscular atrophy (SBMA).

INTRODUCTION: The expansion of a hexanucleotide GGGGCC repeat (G4C2) in the C9orf72 locus is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In addition, C9orf72 expansion has also been detected in patients with a clinical manifestation of Parkinson's Disease (PD), Alzheimer's Disease (AD), Huntington's Disease (HD), and ataxic disorders. MATERIAL AND METHODS: A total of 1,387 patients with clinically suspected ALS, HD or spinal and bulbar muscular atrophy (SBMA) were enrolled, and the prevalence of C9orf72 expansions was estimated. RESULTS: The hexanucleotide expansion accounted for 3.7% of the ALS patients, 0.2% of the HD suspected patients with excluded HTT mutation, and 1.3% of the suspected SBMA patients with excluded mutation in AR gene. CONCLUSIONS: This is the first report revealing the presence of C9orf72 expansion in patients with a suspected SBMA diagnosis. Consequently, we advise testing for C9orf72 expansion in patients presenting with the SBMA phenotype and a genetically unsolved diagnosis.

The role of the dorsal hippocampus in resistance to the development of posttraumatic stress disorder-like behaviours.

This study aimed to determine the activity of the dorsal hippocampus (dHIP) in resistance to the development of posttraumatic stress disorder (PTSD)-like behaviours. Rats were divided into resistant, PTSD(-), and susceptible, PTSD(+) groups based on the time spent in the central area in an open field test and freezing duration during exposure to an aversive context one week after stress experience (electric foot shock). The PTSD(-) rats, compared to the PTSD(+) group, had an increased concentration of corticosterone in plasma and changes in the activity of the dHIP, specifically, increased c-Fos expression in the dentate gyrus (DG) and increased Neuroligin-2 (marker of GABAergic neurotransmission) expression in the DG and CA3 area of the dHIP. Moreover, in the hippocampus, the PTSD(-) group showed decreased mRNA expression for corticotropin-releasing factor receptors type 1 and 2, increased mRNA expression for orexin receptor type 1, and decreased miR-9 and miR-34c levels compared with the PTSD(+) group. This study may suggest that the increase in GABA signalling in the hippocampus attenuates the activity of the CRF system and enhances the function of the orexin system. Moreover, decreased expression of miR-34c and miR-9 could facilitate fear extinction and diminishes the anxiety response. These effects may lead to an anxiolytic-like effect and improve resistance to developing PTSD-like behaviours.

The effects of the recurrent social isolation stress on fear extinction and dopamine D2 receptors in the amygdala and the hippocampus.

BACKGROUND: The present study assessed the influence of recurrent social isolation stress on the aversive memory extinction and dopamine D2 receptors (D2R) expression in the amygdala and the hippocampus subnuclei. We also analyzed the expression of epigenetic factors potentially associated with fear extinction: miRNA-128 and miRNA-142 in the amygdala. METHODS: Male adult fear-conditioned rats had three episodes of 48 h social isolation stress before each fear extinction session in weeks intervals. Ninety minutes after the last extinction session, the D2R expression in the nuclei of the amygdala and the hippocampus (immunocytochemical technique), and mRNA levels for D2R in the amygdala were assessed (PCR). Moreover, we evaluated the levels of miRNA-128 and miRNA-142 in the amygdala. RESULTS: It was found that recurrent social isolation stress decreased the fear extinction rate. The extinguished isolated rats were characterized by higher expression of D2R in the CA1 area of the hippocampus compared to the extinguished and the control rats. In turn, the isolated group presented higher D2R immunoreactivity in the CA1 area compared to the extinguished, the control, and the extinguished isolated animals. Moreover, the extinguished animals had higher expression of D2R in the central amygdala than the control and the extinguished isolated rats. These changes were accompanied by the increase in miRNA-128 level in the amygdala in the extinguished isolated rats compared to the control, the extinguished, and the isolated rats. Moreover, the extinguished rats had lower expression of miRNA-128 compared to the control and the isolated animals. CONCLUSIONS: Our results suggest that social isolation stress impairs aversive memory extinction and coexists with changes in the D2R expression in the amygdala and hippocampus and increased expression of miRNA-128 in the amygdala.

Molecular pattern of a decrease in the rewarding effect of cocaine after an escalating-dose drug regimen.

BACKGROUND: Long-term cocaine exposure leads to dysregulation of the reward system and initiates processes that ultimately weaken its rewarding effects. Here, we studied the influence of an escalating-dose cocaine regimen on drug-associated appetitive behavior after a withdrawal period, along with corresponding molecular changes in plasma and the prefrontal cortex (PFC). METHODS: We applied a 5 day escalating-dose cocaine regimen in rats. We assessed anxiety-like behavior at the beginning of the withdrawal period in the elevated plus maze (EPM) test. The reinforcement properties of cocaine were evaluated in the Conditioned Place Preference (CPP) test along with ultrasonic vocalization (USV) in the appetitive range in a drug-associated context. We assessed corticosterone, proopiomelanocortin (POMC), ß-endorphin, CART 55-102 levels in plasma (by ELISA), along with mRNA levels for D2 dopaminergic receptor (D2R), κ-receptor (KOR), orexin 1 receptor (OX1R), CART 55-102, and potential markers of cocaine abuse: miRNA-124 and miRNA-137 levels in the PFC (by PCR). RESULTS: Rats subjected to the escalating-dose cocaine binge regimen spent less time in the cocaine-paired compartment, and presented a lower number of appetitive USV episodes. These changes were accompanied by a decrease in corticosterone and CART levels, an increase in POMC and ß-endorphin levels in plasma, and an increase in the mRNA for D2R and miRNA-124 levels, but a decrease in the mRNA levels for KOR, OX1R, and CART 55-102 in the PFC. CONCLUSIONS: The presented data reflect a part of a bigger picture of a multilevel interplay between neurotransmitter systems and neuromodulators underlying processes associated with cocaine abuse.