ABSTRACT
The rare A673T variant was the first variant found within the amyloid precursor protein (APP) gene conferring protection against Alzheimer's disease (AD). Thereafter, different studies have discovered that the carriers of the APP A673T variant show reduced levels of amyloid beta (Aß) in the plasma and better cognitive performance at high age. Here, we analyzed cerebrospinal fluid (CSF) and plasma of APP A673T carriers and control individuals using a mass spectrometry-based proteomics approach to identify differentially regulated targets in an unbiased manner. Furthermore, the APP A673T variant was introduced into 2D and 3D neuronal cell culture models together with the pathogenic APP Swedish and London mutations. Consequently, we now report for the first time the protective effects of the APP A673T variant against AD-related alterations in the CSF, plasma, and brain biopsy samples from the frontal cortex. The CSF levels of soluble APPß (sAPPß) and Aß42 were significantly decreased on average 9-26% among three APP A673T carriers as compared to three well-matched controls not carrying the protective variant. Consistent with these CSF findings, immunohistochemical assessment of cortical biopsy samples from the same APP A673T carriers did not reveal Aß, phospho-tau, or p62 pathologies. We identified differentially regulated targets involved in protein phosphorylation, inflammation, and mitochondrial function in the CSF and plasma samples of APP A673T carriers. Some of the identified targets showed inverse levels in AD brain tissue with respect to increased AD-associated neurofibrillary pathology. In 2D and 3D neuronal cell culture models expressing APP with the Swedish and London mutations, the introduction of the APP A673T variant resulted in lower sAPPß levels. Concomitantly, the levels of sAPPα were increased, while decreased levels of CTFß and Aß42 were detected in some of these models. Our findings emphasize the important role of APP-derived peptides in the pathogenesis of AD and demonstrate the effectiveness of the protective APP A673T variant to shift APP processing towards the non-amyloidogenic pathway in vitro even in the presence of two pathogenic mutations.
Subject(s)
Alzheimer Disease , Amyloid beta-Protein Precursor , Humans , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Alzheimer Disease/cerebrospinal fluid , Amyloid beta-Peptides/metabolism , Heterozygote , Brain/metabolismABSTRACT
Accumulation of amyloid ß-peptide (Aß) in the brain of Alzheimer's disease (AD) patients has been postulated to reflect defects in Aß degradation or clearance. Here, we selected 12 genes (MMEL1, ECE1, ECE2, AGER, PLG, PLAT, NR1H3, MMP3, LRP1, TTR, NR1H2, and MMP9) involved in Aß catabolism on the basis of PubMed-based literature search and elucidated their genetic role in AD among Finnish case-control cohort consisting of total â¼1,300 AD patients and control subjects. Thirty one single nucleotide polymorphisms (SNPs) were selected for genotyping. In a smaller subset of AD patients, cerebrospinal fluid (CSF) levels of Aß42 (n = 124), total-tau (n = 59), and phospho-tau (n = 54) analyses were performed with respect to SNPs. Moreover, age of onset analyses with respect to the studied SNPs were conducted among the AD patient cohort (n = 642). Association analysis of the liver X receptor α (NR1H3) gene SNPs showed a protective effect for C allele carriers of rs7120118 (OR = 0.70, 95% CI 0.53-0.93), while the total-tau and phospho-tau levels in CSF were decreased in AD patients carrying the C allele. Also, a decrease in the age of onset was observed in AD patients carrying the A allele of rs723744 and the C allele of rs3794884 in transthyretin (TTR) gene. However, after adjusting the p-values for multiple comparisons, these results were not statistically significant, suggesting that genetic variations in MMEL1, ECE1, ECE2, AGER, PLG, PLAT, NR1H3, MMP3, LRP1, TTR, NR1H2, and MMP9 genes do not play major role among the Finnish AD patient cohort.
Subject(s)
Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/genetics , Amyloid beta-Peptides/metabolism , Age Factors , Age of Onset , Cohort Studies , Female , Finland , Genetic Association Studies , Humans , Liver X Receptors , Male , Orphan Nuclear Receptors/genetics , Peptide Fragments , Polymorphism, Single Nucleotide , Prealbumin/cerebrospinal fluid , Prealbumin/genetics , PubMed/statistics & numerical data , RNA, Messenger/metabolism , tau ProteinsABSTRACT
Alzheimer's disease (AD) is a genetically complex disorder encompassing several individual susceptibility genes with low risk effects. To assess the risk gene effects in a cohort consisting of â¼ 1300 Finnish AD patients and controls, 21 candidate gene polymorphisms were selected for genotyping on the basis of the meta-analyses retrieved from the AlzGene database. A significant genotype and allele association with AD was observed with rs1800629 in the tumor necrosis factor α (TNF). Risk analysis revealed a protective effect for the minor allele carriers of rs1800629. This suggests that genetic alteration in TNF gene may play a role in AD.
