Pleiotropic Protective Effects of Phytochemicals in Alzheimer's Disease

Alzheimer's disease (AD) is a severe chronic neurodegenerative disorder of the brain characterised by progressive impairment in memory and cognition. In the past years an intense research has aimed at dissecting the molecular events of AD. However, there is not an exhaustive knowledge about AD pathogenesis and a limited number of therapeutic options are available to treat this neurodegenerative disease. Consequently, considering the heterogeneity of AD, therapeutic agents acting on multiple levels of the pathology are needed. Recent findings suggest that phytochemicals compounds with neuroprotective features may be an important resources in the discovery of drug candidates against AD. In this paper we will describe some polyphenols and we will discuss their potential role as neuroprotective agents. Specifically, curcumin, catechins, and resveratrol beyond their antioxidant activity are also involved in antiamyloidogenic and anti-inflammatory mechanisms. We will focus on specific molecular targets of these selected phytochemical compounds highlighting the correlations between their neuroprotective functions and their potential therapeutic value in AD

Serum amino acid profiles in normal subjects and in patients with or at risk of Alzheimer dementia

Background/Aims: Abnormalities in the plasma amino acid profile have been reported in Alzheimer disease (AD), but no data exist for the prodromal phase characterized by subjective memory complaint (SMC). It was our aim to understand if serum amino acid levels change along the continuum from normal to AD, and to identify possible diagnostic biomarkers. Methods: Serum levels of 15 amino acids and 2 organic acids were determined in 4 groups of participants – 29 with probable AD, 18 with mild cognitive impairment (MCI), 24 with SMC, and 46 cognitively healthy subjects (HS) – by electrospray tandem mass spectrometry. Results: Glutamate, aspartate, and phenylalanine progressively decreased, while citrulline, argi­ninosuccinate, and homocitrulline progressively increased, from HS over SMC and MCI to AD. The panel including these 6 amino acids and 4 ratios (glutamate/citrulline, citrulline/phenylalanine, leucine plus isoleucine/phenylalanine, and arginine/phenylalanine) discriminated AD from HS with about 96% accuracy. Other panels including 20 biomarkers discriminated SMC or MCI from AD or HS with an accuracy ranging from 88 to 75%. Conclusion: Amino acids contribute to a characteristic metabotype during the progression of AD along the continuum from health to frank dementia, and their monitoring in elderly individuals might help to detect at-risk subjects

ACE and AGTR1 polymorphisms in elite rhythmic gymnastics

In the angiotensin-converting enzyme (ACE) gene, Alu deletion, in intron 16, is associated with higher concentrations of ACE serum activity and this may be associated with elite sprint and power performance. The Alu insertion is associated with lower ACE levels and this could lead to endurance performance. Moreover, recent studies have identified a single-nucleotide polymorphism of the angiotensin type 1 receptor gene AGTR1, which seems to be related to ACE activity. The aim of this study was to examine the involvement of the ACE and the AGTR1 gene polymorphisms in 28 Italian elite rhythmic gymnasts (age range 21 ± 7.6 years), and compare them to 23 middle level rhythmic gymnasts (age range 17 ± 10.9 years). The ACE D allele was significantly more frequent in elite athletes than in the control population (χ(2)=4.07, p=0.04). Comparisons between the middle level and elite athletes revealed significant differences (p<0.0001) for the ACE DD genotype (OR=6.48, 95% confidence interval=1.48-28.34), which was more frequent in elite athletes. There were no significant differences in the AGTR1 A/C genotype or allele distributions between the middle level and elite athletes. In conclusion, the ACE D allele genotype could be a contributing factor to high-performance rhythmic gymnastics that should be considered in athlete development and could help to identify which skills should be trained for talent promotion

Compound BMPR2 gene mutations in a malignant variant of idiopathic pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH; MIM 600799) is frequently associated with concomitant diseases, including congenital heart disease. 6% of patients with PAH show a family history of the disease [hereditary PAH (HPAH)], with the major genetic determinants of HPAH being heterozygous germline mutations in the bone morphogenetic protein type II receptor (BMPR2). We present the case of a 38-year-old woman of Indian descent; initially admitted with progressive dyspnea [New York Heart Association (NYHA) class III]. The results of the proband’s clinical assessments are presented here. Cardiac catheterization confirmed idiopathic PAH with severe right ventricular hypertrophy associated with pulmonary arteriopathy. Initial treatment comprised the dual endothelin receptor antagonist, bosentan, furosemide, warfarin and intravenous infusion of prostaglandin I2 (PGI2) for 3 days. Despite this, the patient died of pulmonary hemorrhagic edema and cardiogenic shock after 6 days of intensive care. After relatives’ consent, post mortem assessments confirmed a diagnosis of PAH; the heart displayed significant right ventricular hypertrophy and it was particularly noted that the right atrial appendage had undergone extreme dilation. Pulmonary arteriopathy was characterized by medial hypertrophy, arterialization of muscular arteries and muscularization of non-muscularized distal arteries. Molecular genetic analyses revealed the presence of cis-mutations in the BMPR2 gene (p.Cys123Arg and p.Arg332X). Cosegregation studies were not available. Our findings suggest that mutations of the BMPR2 gene gave rise to the onset of PAH in this patient and that the severity of the onset and progression could be attributed to the presence of multiple mutations in a genedosage manner

Genetic risk factors and candidate biomarkers for Alzheimer’s disease

Alzheimer's disease is a multifactorial and progressive neurodegenerative disease, extremely diffused and with an increasing prevalence worldwide. There is an urgent need for biomarkers to diagnose AD early in its course. Furthermore, accurate biomarkers would be able to determine the clinical efficacy of novel neuroprotective strategies. Although the heritability of late-onset AD is high, our knowledge of the underlying putative susceptibility genes remains incomplete and the only unequivocally established late-onset AD gene is APOE. Nevertheless a number of susceptibility loci seems to influence the pathogenesis of AD, and variations in numerous genes have been considered to be important in the risk for AD. Many advances have been made in identifying biochemical indices of brain dysfunction, measured in body fluids such as cerebrospinal fluid and plasma, with different methodological approaches. Although these biomarkers are promising, none of them can predict AD with 100% confidence to date. This review will elaborate on the available selection of genetic and biochemical biomarkers for AD, with a particular reference to those linked to inflammation and oxidative stress

Serum Levels of Acyl-Carnitines along the Continuum from Normal to Alzheimer's Dementia

<div><p>This study aimed to determine the serum levels of free L-carnitine, acetyl-L-carnitine and 34 acyl-L-carnitine in healthy subjects and in patients with or at risk of Alzheimer’s disease. Twenty-nine patients with probable Alzheimer’s disease, 18 with mild cognitive impairment of the amnestic type, 24 with subjective memory complaint and 46 healthy subjects were enrolled in the study, and the levels of carnitine and acyl-carnitines were measured by tandem mass spectrometry. The concentrations of acetyl-L-carnitine progressively decreased passing from healthy subjects group (mean±SD, 5.6±1.3 μmol/L) to subjective memory complaint (4.3±0.9 μmol/L), mild cognitive impairment (4.0±0.53 μmol/L), up to Alzheimer’s disease (3.5±0.6 μmol/L) group (p<0.001). The differences were significant for the comparisons: healthy subjects vs. subjective memory complaint, mild cognitive impairment or Alzheimer’s disease group; and subjective memory complaint vs. Alzheimer’s disease group. Other acyl-carnitines, such as malonyl-, 3-hydroxyisovaleryl-, hexenoyl-, decanoyl-, dodecanoyl-, dodecenoyl-, myristoyl-, tetradecenoyl-, hexadecenoyl-, stearoyl-, oleyl- and linoleyl-L-carnitine, showed a similar decreasing trend, passing from healthy subjects to patients at risk of or with Alzheimer’s disease. These results suggest that serum acetyl-L-carnitine and other acyl-L-carnitine levels decrease along the continuum from healthy subjects to subjective memory complaint and mild cognitive impairment subjects, up to patients with Alzheimer’s disease, and that the metabolism of some acyl-carnitines is finely connected among them. These findings also suggest that the serum levels of acetyl-L-carnitine and other acyl-L-carnitines could help to identify the patients before the phenotype conversion to Alzheimer’s disease and the patients who would benefit from the treatment with acetyl-L-carnitine. However, further validation on a larger number of samples in a longitudinal study is needed before application to clinical practice.</p></div