María T. Calatayud

APP Processing and the APP-KPI Domain Involvement in the Amyloid Cascade

Alternative APP mRNA splicing can generate isoforms of APP containing a Kunitz protease inhibitor (KPI) domain. KPI is one of the main serine protease inhibitors. Protein and mRNA KPI(+)APP levels are elevated in Alzheimer’s disease (AD) brain and are associated with increased amyloid beta deposition. In the last years increasing evidence on multiple points in the amyloid cascade where KPI(+)APP is involved has been accumulated, admitting an outstanding position in the pathogenesis of AD to the KPI domain. This review focuses on the APP processing, the molecular activity of KPI and its physiological and pathological roles and the KPI involvement in the amyloid cascade through the nerve growth factor, the lipoprotein receptor-related protein, the tumor necrosis factor-alpha converting enzyme and the Notch1 protein.

Exacerbation of Lewy bodies dementia due to memantine.

INTRODUCTION Lewy body dementia (DLB) is common but frequently misdiagnosed as Alzheimers disease plus delirium or parkinsonism. DRUGS USED IN THIS DISORDER CAN CAUSE EXACERBATIONS: neuroleptic medication is relatively contraindicated because some patients show severe neuroleptic sensitivity, antiparkinsonian medication has the potential to exacerbate psychotic symptoms, and even cholinesterase inhibitors, while relatively safe, have provoked adverse responses in some DLB patients. There are few data available about the use of memantine in DLB. CASE PRESENTATION A 74-year-old man was diagnosed with Alzheimer disease and parkinsonism. After memantine was started he developed severe fluctuations in awareness, visual hallucinations, agitation, and worsened parkinsonism. When he was evaluated thoroughly, the diagnosis was revised to Lewy body dementia, leading to changes in treatment that were associated with dramatic improvement in the patients mental status. CONCLUSIONS In our patient, motor and cognitive symptoms worsened with memantine treatment; these resolved after memantine was discontinued.

Late-onset Alzheimer's disease is associated with mitochondrial DNA 7028C/haplogroup H and D310 poly-C tract heteroplasmy

There is growing evidence that mitochondria play an important role in the pathogenesis of late-onset Alzheimers disease (LOAD) [1]. Certain haplogroups defined by combinations of common mitochondrial DNA (mtDNA) single-nucleotide polymorphisms (SNPs) have been associated with longevity and age-related diseases. Recent studies reported a significant association between haplogroup H and LOAD [2–4] (supplementary Table 1). Differences between the mtDNA SNPs/haplogroups in the efficiency of oxygen consumption and ATP and ROS production could partly explain these associations [5]. Although the relative risk attributed to this haplogroup was low (<1.5) in all the studies, this could have important implications considering the high incidence of LOAD at the population level. It is therefore very important to determine the influence of mtDNA polymorphisms in LOAD by studying large cohorts from different populations. We report the results from Asturias (northern Spain) based on a total of 500 LOAD patients and 500 controls (Supplementary file). The mtDNA 7028C was significantly more frequent among the patients (p=0.001; OR=1.52, 95% CI=1.18– 1.95; Table 1). Allele frequencies for the other six SNPs that defined the mitochondrial haplogroups did not differ between patients and controls (data not shown). Haplogroup H (defined by 7028C) was significantly more frequent among the patients (Supplementary file). Multiple logistic regression with apolipoprotein E gene (APOE)-ε4 and mtDNA 7028C status, age, and gender as covariates showed that APOE-ε4 and 7028C were associated with LOAD. We found a synergistic effect between the two risk variants: the OR for APOE-ε4 + 7028C (OR=5.30, 95% CI=3.72–7.54) was higher than the OR for each separately. The non-APOE-ε4 + 7028T had a protective effect (OR= 0.43; 95%CI=0.33–0.75). Patients and controls were classified as D310 7C or D310 >7C (poly-C tract at position 310 of the mtDNA, Supplementary file). We found a significantly higher frequency of the >7C alleles among the patients (Table 1). Electronic supplementary material The online version of this article (doi:10.1007/s10048-011-0295-4) contains supplementary material, which is available to authorized users. E. Coto (*) : J. Gómez :B. Alonso :A. I. Corao :M. Díaz : V. Álvarez Genética Molecular-Laboratorio de Medicina, Hospital Universitario Central Asturias, 33006 Oviedo, Spain e-mail: eliecer.coto@sespa.princast.es

Value of Measuring Plasmatic Levels of Neurosin in the Diagnosis of Alzheimer's Disease

The search for molecular biomarkers for diagnosing and classifying dementias is becoming a high priority need. Neurosin (Kallikrein 6, hk6) is one molecule with promising preliminary results since its levels in brain tissue, cerebrospinal fluid and blood have been found to be abnormal in Alzheimers disease (AD). In this study, we measured plasmatic levels of neurosin in healthy individuals and patients with cognitive symptoms independently of what the final diagnosis was. We collected plasma samples from 228 controls and 447 patients finally diagnosed with either AD, Mild Cognitive Impairment, Dementia with Lewy Bodies or Parkinson-Dementia, Frontotemporal Dementia, Huntingtons disease, Primary Progressive Aphasia, Corticobasal degeneration, Creutzfeldt-Jakobs disease or Pseudodementia. We found that plasmatic levels of neurosin increase with age in healthy individuals and decrease in patients with AD. Plasmatic levels of neurosin differ significantly between AD and Vascular Dementia, Pseudodementia and the control group. Analyses comparing any other form of neurodegenerative dementia to the AD group did not show significant differences. In conclusion, measurement of plasmatic levels of neurosin is useful to distinguish AD patients from subjects without neurodegenerative dementia (either Pseudodementia, Vascular Dementia or controls) although it is not useful to distinguish among neurodegenerative dementias.

Myocyte enhancing factor-2A in Alzheimer's disease: genetic analysis and association with MEF2A-polymorphisms.

Polymorphisms at different genes have been proposed as determinants of the risk for developing late-onset Alzheimers disease (LOAD). Among the several candidate genes are those that encode proteins involved in neuronal degeneration/survival. Studies of primary neuronal cultures supported that members of the myocyte enhancing factor-2 (MEF2) family of transcription factors have an anti-apoptotic effect, regulating the expression of proteins involved in neuronal survival and differentiation. We analysed the MEF2A gene in a total of 357 patients (mean age 72 years, range 60-97 years). Among others, a Pro279Leu in exon 8 and a polyglutamine (CAG) repeat polymorphisms in exon 12 were found. These variants were also genotyped in 495 healthy controls (>50 years old), and the frequencies were statistically compared. Eight patients were 279L (six P/L and two L/L), compared to only one control (2% vs. 0.2%; p=0.004, OR=11.32). There was a significantly higher frequency of 279L-carriers among APOE epsilon4+ (7/154=4.5%), compared to epsilon4- (1/203) (p=0.02). In conclusion, our work suggests that the variation at the MEF2A gene could be involved in the risk of developing LOAD. Because MEF2 has been related with neuronal survival, and the 279L allele has been related with a reduction in the transcriptional activation activity of MEF2A, the effect of this allele could be mediated through a down-regulation of antiapoptotic genes.

Plasmatic level of neurosin predicts outcome of mild cognitive impairment.

Background Mild Cognitive Impairment (MCI) is a disorder considered to be a transitional stage from health to dementia. Diagnosis of dementias at these early stages is always troublesome because the pathophysiologic events leading to dementia precede clinical symptoms. Thus, the development of biomarkers that can be used to support the diagnosis of dementias at early stages is rapidly becoming a high priority. We have recently reported the value of measuring plasmatic levels of neurosin in the diagnosis of Alzheimers disease (AD). The aim of this study is to determine whether measuring plasmatic concentration of neurosin is a valuable test to predict progression of MCI. Methods Plasmatic neurosin concentrations were measured in 68 MCI patients and 70 controls subjects. Blood samples were obtained at the beginning of the study. Sixty six patients diagnosed with MCI were observed for 18 months. In 36 patients a second blood sample was obtained at the endpoint. Results The mean value of plasmatic neurosin concentration differs significantly between MCI patients who converted to Dementia with vascular component, those who converted to AD, or those who remained at MCI stage. The relative risk of developing Dementia with vascular component when neurosin levels are higher than 5.25 ng/ml is 13 while the relative risk of developing mild AD when neurosin levels are lower than 5.25 ng/ml is 2. Increases in the levels of neurosin indicate progression to Dementia with vascular component. Conclusion The measurement of plasmatic neurosin level in patients diagnosed with MCI may predict conversion from MCI to Dementia with vascular component. A single measurement is also valuable to estimate the risk of developing AD and Dementia with vascular component. Finally, repeated measurement of plasmatic neurosin might be a useful test to predict outcome in patients with MCI.

Amyloid Precursor Protein Gene (APP) Variation in Late-Onset Alzheimer’s Disease

Mutations in the beta-amyloid precursor protein gene (APP) have been found in familial early-onset Alzheímer’s disease (AD). DNA variants at several genes have been linked to the risk of developing the most common late-onset form of AD (LOAD). A few studies analyzed the contribution of APP variants to LOAD, with negative or conflicting results. We determined the variation in the 18 APP exons and flanking intronic sequences in a total of 350 LOAD patients from Spain. A total of 13 nucleotide changes were found and 6 were new and not found among 340 healthy controls, including the only missense change (D243N). The in silico analysis suggested that none of them would have an effect on pre-mRNA splicing or protein folding (D243N). Patients and controls were also genotyped for three APP promoter polymorphisms, and none of them was significantly associated with LOAD. We concluded that APP variants would not contribute to the risk of developing LOAD in our population.