ABSTRACT
Alzheimer disease (AD) is characterized by progressive cognitive decline caused by synaptic dysfunction and neurodegeneration in the brain, and late-onset AD (LOAD), genetically classified as a polygenetic disease, is the major form of dementia in the elderly. It has been shown that beta amyloid, deposited in the AD brain, interacts with dynamin 1 and that the dynamin 2 (DNM2) gene homologous to the dynamin 1 gene is encoded at chromosome 19p13.2 where a susceptibility locus has been detected by linkage analysis. To test the genetic association of LOAD with the DNM2 gene, we performed a case-control study of 429 patients with LOAD and 438 sex- and age-matched control subjects in a Japanese population. We found a significant association of LOAD with single nucleotide polymorphism markers of the DNM2 gene, especially in non-carriers of the apolipoprotein E-epsilon4 allele. Even though subjects with the genotype homozygous for the risk allele at rs892086 showed no mutation in exons of the DNM2 gene, expression of DNM2 mRNA in the hippocampus was decreased in the patients compared to non-demented controls. We propose that the DNM2 gene is a novel susceptibility gene for LOAD.
Subject(s)
Alzheimer Disease/genetics , Dynamin II/genetics , Genetic Predisposition to Disease/genetics , Genotype , Humans , Linkage Disequilibrium , Polymorphism, Single Nucleotide , Sequence Analysis, DNAABSTRACT
We scanned throughout chromosome 21 to assess genetic associations with late-onset Alzheimer disease (AD) using 374 Japanese patients and 375 population-based controls, because trisomy 21 is known to be associated with early deposition of beta-amyloid (Abeta) in the brain. Among 417 markers spanning 33 Mb, 22 markers showed associations with either the allele or the genotype frequency (P < 0.05). Logistic regression analysis with age, sex and apolipoprotein E (APOE)-epsilon4 dose supported genetic risk of 17 markers, of which eight markers were linked to the SAMSN1, PRSS7, NCAM2, RUNX1, DYRK1A and KCNJ6 genes. In logistic regression, the DYRK1A (dual-specificity tyrosine-regulated kinase 1A) gene, located in the Down syndrome critical region, showed the highest significance [OR = 2.99 (95% CI: 1.72-5.19), P = 0.001], whereas the RUNX1 gene showed a high odds ratio [OR = 23.3 (95% CI: 2.76-196.5), P = 0.038]. DYRK1A mRNA level in the hippocampus was significantly elevated in patients with AD when compared with pathological controls (P < 0.01). DYRK1A mRNA level was upregulated along with an increase in the Abeta-level in the brain of transgenic mice, overproducing Abeta at 9 months of age. In neuroblastoma cells, Abeta induced an increase in the DYRK1A transcript, which also led to tau phosphorylation at Thr212 under the overexpression of tau. Therefore, the upregulation of DYRK1A transcription results from Abeta loading, further leading to tau phosphorylation. Our result indicates that DYRK1A could be a key molecule bridging between beta-amyloid production and tau phosphorylation in AD.
Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Peptides/biosynthesis , Chromosomes, Human, Pair 21/genetics , Down Syndrome/genetics , Membrane Proteins/metabolism , Protein Serine-Threonine Kinases/genetics , Protein-Tyrosine Kinases/genetics , Aged , Aged, 80 and over , Alzheimer Disease/genetics , Animals , Brain/metabolism , Case-Control Studies , Cell Line, Tumor , Female , Haplotypes , Humans , Male , Mice , Mice, Transgenic , Middle Aged , Phosphorylation , Polymorphism, Single Nucleotide , Protein Serine-Threonine Kinases/metabolism , Protein-Tyrosine Kinases/metabolism , RNA, Messenger/metabolism , Dyrk KinasesABSTRACT
Lipid metabolism in the central nervous system has been focused as an important factor of Alzheimer's disease, since the apolipoprotein E gene was discovered as a genetic risk for the disease. Lipid metabolism in the brain, showing relatively closed environment, necessitates lipid reutilization. Cerebrospinal fluid contains only high-density lipoproteins composed of apoE and apoJ secreted from astrocytes and of apoA-I and apoA-II transported via the blood brain barrier. These apolipoproteins can bind to beta amyloid and possibly relate to its clearance. The aggregation of phosphorylated tau, found in neurofibrillary tangles in Alzheimer's brain, is also found in the brain with Niemann-Pick disease, suggesting that the impairment of lipid transport in neuronal cells participates in Alzheimer's disease. Mitochondrial function, lipid production, and acetylcholine production are closely related, and these alterations could be involved in cholinergic dysfunction in Alzheimer's disease. The regulation of lipid metabolism in and outside the brain could be a therapeutic and preventive target for Alzheimer's disease.
