RESUMO
BACKGROUND: Copy number variations (CNVs) play an important role in the genetic etiology of various neurological disorders, including Alzheimer's disease (AD). Type 2 diabetes mellitus (T2DM) and major depressive disorder (MDD) were shown to have share mechanisms and signaling pathways with AD. OBJECTIVE: We aimed to assess CNVs regions that may harbor genes contributing to AD, T2DM, and MDD in 67 Saudi familial and sporadic AD patients, with no alterations in the known genes of AD and genotyped previously for APOE. METHODS: DNA was analyzed using the CytoScan-HD array. Two layers of filtering criteria were applied. All the identified CNVs were checked in the Database of Genomic Variants (DGV). RESULTS: A total of 1086 CNVs (565 gains and 521 losses) were identified in our study. We found 73 CNVs harboring genes that may be associated with AD, T2DM or MDD. Nineteen CNVs were novel. Most importantly, 42 CNVs were unique in our studied cohort existing only in one patient. Two large gains on chromosomes 1 and 13 harbored genes implicated in the studied disorders. We identified CNVs in genes that encode proteins involved in the metabolism of amyloid-ß peptide (AGRN, APBA2, CR1, CR2, IGF2R, KIAA0125, MBP, RER1, RTN4R, VDR and WISPI) or Tau proteins (CACNAIC, CELF2, DUSP22, HTRA1 and SLC2A14). CONCLUSION: The present work provided information on the presence of CNVs related to AD, T2DM, and MDD in Saudi Alzheimer's patients.
Assuntos
Doença de Alzheimer/genética , Variações do Número de Cópias de DNA , Transtorno Depressivo Maior/genética , Diabetes Mellitus Tipo 2/genética , Idoso , Precursor de Proteína beta-Amiloide , Proteínas CELF/genética , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genéticaRESUMO
BACKGROUND: Alzheimer's disease (AD) is a chronic neurological disorder associated with mental decline and dementia. Several studies focused on investigating the molecular basis of the disease that led to the identification of several causative genes and risk associated alleles. Replication of these studies and findings from different populations is very important. OBJECTIVE: Molecular assessment of a cohort of 117 familial and sporadic AD cases from Saudi Arabia. METHODS: Comprehensive screening for point mutations was carried out by direct sequencing of coding regions in the three known AD causative genes: PSEN1, PSEN2, APP, as well as the AD associated gene SORL1. All patients were also genotyped for APOE alleles. In silico 3D protein structure analysis was performed for two novel SORL1 variants. RESULTS: We identified a total of eight potential pathogenic missense variants in all studied genes. Five of these variants were not previously reported including four in SORL1 (p.Val297Met, p.Arg1084Cys, p.Asp1100Asn, and p.Pro1213Ser) and one in APP (p.Glu380Lys). The frequency of APOE-É4 allele was 21.37% of total investigated cases. In silico 3D protein structure analysis of two SORL1 novel missense variants (p.Pro1213Ser and p.Arg1084Cys) suggested that these variants may affect the folding of the proteins and disturb their structure. CONCLUSIONS: Our comprehensive analysis of the open reading frame of the known genes have identified potential pathogenic rare variants in 18/117 cases. We found that point mutations in AD main genes (PSEN1, PSEN2, and APP) were underrepresented in our cohort of patients. Our results confirm involvement of SORL1 in familial and sporadic AD cases.
Assuntos
Doença de Alzheimer/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Precursor de Proteína beta-Amiloide/genética , Apolipoproteínas E/genética , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Proteínas Relacionadas a Receptor de LDL/genética , Masculino , Proteínas de Membrana Transportadoras/genética , Pessoa de Meia-Idade , Estrutura Molecular , Mutação de Sentido Incorreto/genética , Linhagem , Mutação Puntual/genética , Presenilina-1/genética , Presenilina-2/genética , Arábia Saudita , Adulto JovemRESUMO
RATIONALE: Pregnenolone sulfate (PREGS) and dehydroepiandrosterone sulphate (DHEAS) are pro-amnesic, anti-amnesic and neuroprotective steroids in rodents. In Alzheimer's disease (AD) patient's brains, their low concentrations are correlated with high levels of Aß and tau proteins. The unnatural enantiomer ent-PREGS enhanced memory in rodents. We investigated here whether ent-PREGS and ent-DHEAS could be neuroprotective in AD models. OBJECTIVE: The effects of PREGS, ent-PREGS, DHEAS and ent-DHEAS against Aß25-35 peptide-induced toxicity were examined in vitro on B104 neuroblastoma cells and in vivo in mice. METHODS: B104 cells pretreated with the steroids before Aß25-35 were analysed by flow cytometry measuring cell viability and death processes. Mice injected intracerebroventricularly with Aß25-35 and the steroids were analysed for their memory abilities. Additionally, lipid peroxidation levels in the hippocampus were measured. RESULTS: ent-PREGS and PREGS significantly attenuated the Aß25-35-induced decrease in cell viability. Both steroids prevented the Aß25-35-induced increase in late apoptotic cells. PREGS further attenuated the ratio of necrotic cells. ent-DHEAS and DHEAS significantly reduced the Aß25-35-induced toxicity and prevented the cells from entering late apoptosis and necrosis. All steroids stimulated neurite outgrowth per se and prevented the Aß25-35-induced decrease. In vivo, ent-PREGS and ent-DHEAS significantly attenuated the Aß25-35-induced decrease in memory (spontaneous alternation and passive avoidance) and an increase in lipid peroxidation levels. In contrast to the natural steroids, both enantiomers prevented amnesia when injected 6 h before Aß25-35 in contrast to the natural steroids. CONCLUSION: The unnatural steroids ent-PREGS and ent-DHEAS are potent neuroprotective agents and could be effective therapeutical tools in AD.
